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Abstract

Diabetes mellitus is a multifactorial hyperglycemic condition characterized by biochemical, molecular, and genetic variables, and leads to kidney dysfunction. Diabetic nephropathy (DN), referred to as diabetic kidney disease, is one of the major microvascular complications of diabetes, which is a major cause of end-stage renal disease and, consequently, high mortality. When DN occurs, it stimulates the renin-angiotensin system (RAS), one of the most significant indicators of developing renal impairment. Intrarenal RAS elements are upregulated in patients with DN, whereas systemic RAS elements are downregulated. Therefore, it is well accepted that the intra-renal RAS plays a key role in the onset of DN, characterized by the presence of protein in the urine and progressive decline in kidney function. RAS has two axes: 1- the renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and Ang II type 1 receptor (AT₁R), 2- (ACE2, Ang 1-7, Ang 1-9, AT ₂ receptor (AT₂R), and Mas receptor (MasR). Blocking RAS with ACE inhibitors (ACEIs) and Ang II receptor blockers (ARBs) is currently a conventional therapy to protect the kidneys and inhibit DN progression and development in people with type 1 and type 2 diabetes.

Keywords

diabetic nephropathy renin-angiotensin system angiotensin II angiotensin-converting enzyme angiotensin 1-7

Introduction

Diabetic nephropathy (DN), also referred to as diabetic kidney disease (DKD), is a major microvascular consequence of diabetes. It is a prominent cause of end-stage renal disease (ESRD) and has a high mortality rate due to damage to the glomeruli and tubules.^1–3 According to epidemiological studies, roughly 8.8% of individuals had diabetes in 2015, and by 2024, that number would increase to 10.4%.⁴ Both type 1 diabetes (T1D) and type 2 diabetes (T2D) can cause nephropathy; however, a lesser percentage of people with T2D go on to develop ESRD. Because T2D is more common, these individuals make up more than half of the diabetics receiving hemodialysis.⁵ Previous epidemiological research revealed that DN can develop in 25% to 40% of patients with T1D and 5% to 40% of those with T2D.² The early phase of DN is marked by normoalbuminuria and normal glomerular filtration rate (GFR), which develops within 5–10 years and is frequently associated with tubular and glomerular hypertrophy and enlarged kidneys, accompanied by microalbuminuria, which advances in 5–15 years and is marked by urinary excretion of albumin of 30 mg to 300 mg albumin/24 h creatinine.⁶ The latter stage of DN, known as macroalbuminuria or explicit proteinuria, occurs in 10 to 20 years and is defined by urinary excretion of albumin values more of than 300 mg albumin/ 24 h of creatinine. DN advances to ESRD with continued GFR reduction, which typically occurs within 15 to 25 years. Usually, ESRD appears 5 years after the onset of nephrotic phase proteinuria.^6,7 The pathogenesis of ESRD in diabetes comprises many profibrotic and proinflammatory processes that are stimulated by hyperglycemia. This breaks down the glomerular filtration barrier, hurts podocytes, makes the mesangial matrix bigger, causes tubulointerstitial fibrosis, and lowers GFR. A loss of renal glomerular barrier integrity leads to albuminuria and exacerbates the effects of tubulointerstitial fibrosis.⁸

In patients with DN, intrarenal renin angiotensin system (RAS) elements are upregulated, whereas systemic RAS elements are downregulated.⁹ Therefore, it is well accepted that the intra-renal RAS plays a key role in the onset of DN, which is marked by protein in the urine and a progressive decline in kidney function.¹⁰ RAS has two axes: 1- the renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT₁R), 2- (ACE2, Ang 1-7, Ang 1-9, AT ₂ receptor (AT₂R), and Mas receptor (MasR)¹¹ Imbalanced RAS activation and an inappropriately active ACE/Ang II axis are the key effectors that can lead to the beginning and development of renal injury.¹² Ang II, additionally to its primary role as a hemodynamic mediator, as a cytokine, through stimulating systemic and local RAS raised glomerular capillary pressure and permeability (generating proteinuria), hypertrophy, proliferation of renal cells, and extracellular matrix (ECM), cytokine production, inflammation, macrophage infiltration, and eventually harm to the kidneys.^9,13,14 Blocking RAS with ACE inhibitors (ACEIs) and Ang II receptor blockers (ARBs) is currently a conventional therapy to protect the kidneys and inhibit the development and progression of DN in T1D and T2D.^15–17 RAS inhibitors are included in the mainstay treatments of DN along with sodium-glucose co-transporter 2 (SGLT2) inhibitors, incretin-based therapeutic agents, and non-steroidal Mmineralocorticoid receptor antagonists (the diabetic kidney disease fantastic four).¹⁸

Renin angiotensin system in the kidney

The RAS is made up of two classical and non-classical axes that are a collection of enzymes and peptides whose major role is to control blood pressure, and the balance of electrolytes and fluids.¹⁹ The classic or systemic RAS includes the ACE/Ang II/AT₁R axis, begins with renin generated by the juxtaglomerular apparatus that converts angiotensinogen (AGT) to Ang I, and then further Ang I transformed to Ang II via ACE available in lung endothelial cells.^20,21 In the systemic RAS, Ang II, the primary physiological peptide, via binding to AT₁R stimulates reactive oxygen species (ROS) production, vasoconstriction, cell proliferation, hypertrophy, oxidative stress, and fibrosis, all of which contribute to the progression of kidney damage^15,22 (Figure 1).

Figure 1.

Components of the renin angiotensin system.

The non-classical RAS consists of the Ang II/AT₂R and the ACE2-Ang 1-7/MasR axes. ACE2 transforms Ang II into Ang 1-7, which interacts with MasR as an antagonist of AT₁R and induces a reno-protective effect in numerous kidney disorders, like acute kidney injury (AKI), hypertension and DN, glomerulonephritis, and tubulointerstitial fibrosis.²³ The ACE2/Ang1-7 axis frequently counteracts the effects of the Ang II/AT₁R axis by increasing prostaglandins and nitric oxide (NO), facilitating vasodilation, diuresis, natriuresis, and reducing oxidative stress. However, rising data indicates that non-classical RAS components participate in the therapeutic-purpose blockage of the classical system, which lowers blood pressure, attenuates a variety of kidney damage indicators, and supports normal renal function²⁴ (Figure 1).

The nephron's interstitial and intratubular regions contain all the components necessary for the formation of intrarenal Ang II, making the renal RAS unique.²⁵ Renal cells can make renin, renin receptors, Ang receptors, and Ang II on their own, without the help of systemic RAS.⁷ Proximal tubular cells show renin mRNA and renin-like activity.²⁶ The brush border of proximal tubules abundantly expresses ACE mRNA and protein.²⁷ ACE has been found in both the proximal, distal tubular, and collecting ducts fluids, with greater quantities seen in the proximal tubule fluid.²⁷ AT₂R mRNA is found in several vascular and tubular regions of the medulla and cortex, like the proximal tubule, collecting duct, afferent arterioles, arcuate arterioles, and outer medullary descending vasa recta.²⁸ Furthermore, it has been observed that ACE2 is abundantly expressed in tubular cells of the kidney.²⁹ MasR was also detected in the renal cortex, thick ascending loop of Henle, proximal tubule, collecting duct, afferent arteriole, tubular epithelium, and mesangial cells.³⁰ The kidney can also convert Ang I into Ang II. Thus, all components required to generate intrarenal Ang II exist throughout the nephron.³¹

Renin in diabetic nephropathy

As a prohormone, renin releases to produce active renin, the rate-limiting enzyme that regulates renal, volume and salt homeostasis.³² Prorenin is generated by the kidney's juxtaglomerular cells in response to a range of stimuli, involving lower renal perfusion pressure, sympathetic activity, and diminished tubular salt supply in the maculadensa.³³ In spontaneous or streptozotocin-induced diabetic rat models, proximal tubular and juxtaglomerular cells exhibit enhanced renin protein and mRNA levels, accompanied by elevated Ang II levels.³⁴ DN is characterized by elevated intrarenal RAS activity, and decreased plasma renin.⁹ Elevated urinary renin levels in T1D patients with DN and streptozotocin-induced T1D mice are associated with higher GFR and decreased proximal tubular reabsorption in DKD patients.³⁵ Although ARBs and ACEIs are presently the most commonly utilized treatment medications for DN due to their antihypertensive and antiproteinuric properties, Direct renin inhibitors (DRIs) work by targeting the RAS's rate-limiting enzyme. This makes system suppression stronger and treatment outcomes better in DN.³⁶ Aliskiren (renin inhibitor) therapy in diabetic rats exposed to STZ reduces albuminuria and glomerulosclerosis without lowering blood pressure. Additionally, aliskiren-treated diabetic transgenic rats showed a greater reduction in tubulointerstitial fibrosis than rats treated with perindopril (ACEI).³⁷ Aliskiren lowered proteinuria and blood pressure independently in DN individuals.³⁸ In the early stages of diabetes, being exposed to mild hyperglycemia without glycosuria for a short time has been linked to an increase in plasma renin activity, renal vascular resistance, and mean arterial pressure, along with activity of the circulating and local RAS.³³ Long-term use of ACEIs or angiotensin receptor blockers (ARBs) increase renin activity. Thus, direct suppression of renin activity offers potential benefits over ACEIs and ARBs.³⁹ Aliskiren lowers plasma renin activity while increasing renin levels. As a result, when compared to ACEI/ARBs, aliskiren may generate a more complete RAS blockage and diminish compensatory feedback.³⁹ Using aliskiren and losartan (an AT₁R antagonist) together to block the RAS decreased albuminuria by 20% more than just losartan alone. Thus, renin blockers may be useful in slowing the progression of DN.⁴⁰ Aliskiren therapy in DN patients lowers blood pressure, oxidative stress, urine albumin-to-creatinine ratio, inflammatory cytokine (IL-6) excretions and inflammatory chemokine [monocyte chemoattractant protein-1 (MCP-1)] and raises GFR.⁴¹

Angiotensinogen in diabetic nephropathy

The liver primarily generates AGT, a glycosylated protein, and releases it into the plasma. It cannot cross the glomerular membrane due to its molecular size and protein binding. Intrarenal AGT mRNA and protein, on the other hand, are located in proximal tubular cells. AGT appears to enter the tubules directly and produces its own metabolites within the cells. Therefore, it is believed that the kidney's proximal tubular cells produce locally generated urine AGT (uAGT). People with chronic kidney disease (CKD), like T1D and T2D, have demonstrated higher uAGT levels.^42,43 There is a negative link between the amount of sodium excreted in the urine and blood pressure, uAGT, albumin creatinine ratio (ACR), and estimated GFR (eGFR). This suggests that uAGT levels may be a very good early indicator for RAS activation in DN. Compared to healthy subjects, uAGT increased in macroalbuminuria, microalbuminuria, and normoalbuminuria T2D. The appearance of uAGT in DN prior to albuminuria may be a sign of tubular injury and intrarenal RAS activation in normoalbuminuric T2D patients.^17,44,45 Urinary albumin (UAlb) excretion, which serves as an indicator of DN, raised 6 days after STZ administration, but uAGT excretion rose earlier. The use of insulin abolished the rise. Because insulin reduced uAlb and uAGT excretion, it is assumed that higher glucose levels caused enhanced uAlb and uAGT excretion.⁴⁶ A prospective cohort research study examining injury indicators like uAGT, urine cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), and KIM-1 in addition to albuminuria to forecast the combined result, comprising reduced GFR and ESRD in patients with T2D and nephropathy, showed that uAGT, urine cystatin-C, NGAL, and KIM-1 were substantially linked to an abrupt reduction in kidney function or the development of ESRD. In patients with T2D and nephropathy, the efficiency of these biomarkers was similar to that of conventional urinary albumin (AUC 0.6-0.7).⁴⁷ Taken together, uAGT is a potential urine biomarker for the beginning phases of DN in T2D and T1D patients.⁴⁸

Angiotensin II in diabetic nephropathy

Ang II, the principal bioactive peptide in RAS, is an eight-amino acid peptide that predominantly operates via two particular G-protein-coupled receptors, including AT₁R and AT₂R.⁴⁹ Diabetes-related complications frequently express both receptors.⁵⁰ Chronically high blood glucose levels trigger the activation of Ang-II, leading to increased pressure-induced kidney damage. This activation also changes renal fibroblasts into myofibroblasts, which makes the profibrotic cytokine transforming growth factor beta (TGF-β). Additionally, it induces oxidative stress, stimulates the release of chemokines and osteopontin, which promote local inflammation, and triggers the proliferation and enlargement of vascular and mesangial cells.⁵¹

Ang II has tubular, vascular, and growth-promoting functions in the kidney.⁵² Depending on the dose, extra Ang II infusion lowers GFR and renal blood flow (RBF) and contracts efferent and afferent arterioles.⁵² In addition, Ang II is an inflammatory peptide and an active growth regulator that contributes to the pathophysiology of a number of vascular problems, including DN.³⁴ Experimental studies on diabetic animals have shown increased, decreased, or constant renal Ang II levels. In these investigations, renal Ang II values were measured at the start of diabetes without nephropathy; nevertheless, as DN advances and develops, the amount of renal Ang I and Ang II significantly increased.⁵³ Diabetic hyperglycemia causes the kidneys (especially mesangial cells and proximal tubule cells) to produce more Ang II and AGT, respectively.³⁴ Ang II induces TGF-β secretion, resulting in increased generation and reduced breakdown of matrix proteins that cause glomerular sclerosis, fibrosis, and finally DN.³⁴ Mesangial cells exposed to high-glucose medium or Ang II exhibit increased production of matrix proteins and decreased activity of degradative enzymes such as collagenase and plasmin. Both glucose and Ang II have the ability to hinder proximal tubule proteinases. Glucose stimulates the AGT gene expression in cells located in the proximal tubules and promotes the synthesis of Ang II in primary mesangial cell culture. This suggests that elevated glucose levels may directly activate the RAS. TGF-β may have a role in mediating the impacts of Ang II and glucose on mesangial matrix metabolism. Mesangial cells exposed to glucose or Ang II exhibit elevated levels of TGF-β expression and release. Their impacts on matrix metabolism may be inhibited by anti-TGF-β antibody or ARBs like losartan, which in turn inhibits the increase in TGF-β production caused by glucose.⁵⁴

Ang II contributes to the development of nephrosclerosis and renal fibrosis in diabetes by stimulating the production of aldosterone in the adrenal gland.⁵⁵ Elevated Ang II concentrationin DN stimulates immune cells and cause the generation of chemokines, resulting in additional renal damage. In addition, diabetes also makes kidney disease more likely because it raises levels of ACE and Ang II in interstitial, tubular, and fibroblast-like cells, as well as inflammatory compounds targeting tubular cells.⁵⁶ Ang II raises vascular endothelial growth factor (VEGF) levels, which in turn raises TGF-β levels, increases the production of IV and VI collagens, fibronectin, and laminin, improves endothelial fenestrations, elevates NO generation, permeability, and vasodilation, and causes glomerular endothelial and mesangial cells to differentiate and multiply. These events lead to the glomerular filtration barrier (GFB) breaking down, the glomerular basement membrane (GBM) getting bigger and thicker, proteinuria, microvascular hyperpermeability, and finally a reduction in GFR.⁵⁷

In DN, Ang II causes hyperglycemia, activation of nuclear factor kappa β (NF-κβ), and then expression of toll-like receptor 4 (TLR4), which controls immune responses and the release of inflammatory cytokines.⁵⁸ Ang-II and aldosterone cause cellular insulin resistance in DN individuals by changing insulin signaling and elevating oxidative stress. Additionally, Ang-II causes apoptosis, inflammation, and oxidative stress in pancreatic β-cells.⁵⁹ Findings also pointed to aldosterone's role in the pancreas’ reduced ability to secrete insulin in response to glucose.⁶⁰

The raised renal vasodilator response to captopril and eprosartan in hyperglycemia shows that hyperglycemia causes a boost in renal vascular tone via Ang II. This might happen because of enhanced reactivity, which can be indirect or direct, relying on the input of various systems like the baroreflex arc and the autonomic nervous system, both of which are dysfunctional in diabetes.⁶¹ Systemic Ang II administration raises diabetic glomerular filter permeability, which might be attributed to Ang II's impact both directly and indirectly on podocyte function. Ang II affects podocyte function by producing and accumulating ROS from mitochondrialROS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Furthermore, enhanced intrarenal expression of Ang II receptors makes DKD more susceptible to the damaging impacts of Ang II. High blood pressure and problems with renal autoregulation caused by Ang II can also make diabetic glomerular porosity worse.⁵³ Ang II is also related to insulin resistance because it inhibits insulin receptor-dependent PI3K signaling. Furthermore, Ang II is capable of acting on the AT₁R, reducing insulin-induced NO generation while activating NADPH oxidase, increasing the creation of additional ROS and inflammation.⁶²

Ang II type 1 receptor in diabetic nephropathy

Ang II acts via two functional receptors, namely AT₁R and AT₂R.¹¹ The kidney's proximal tubule, cortical collecting duct, basolateral membranes, and vascular smooth muscle cells throughout the renal vascular system, comprising the efferent and afferent arterioles express AT₁R.^11,23 Ang II's harmful effects on the body happen through the AT₁R and include making aldosterone, reabsorbing sodium into the kidneys, constriction of blood vessels, adrenergic stimulation, vascular remodeling (hypertrophy, inflammation, and fibrosis), and increasing thirst.Ang II/AT₁R activates pathological signaling cascades by stimulating receptor and non-receptor tyrosine kinases, mitogen-activated protein kinases (MAPKs) and serine/threonine kinases, including up-regulation of beneficial and pro-inflammatory genes such as interstitial cell adhesion molecule- 1 (ICAM-1), vascular cell. adhesion molecule-1 (VCAM-1), TGF-β, interleukin-6 (IL-6), and plasminogen activator inhibitor-1 (PAI-1) in DN.³⁴ In STZ-induced diabetic C57BL/6 mice, neither Ang II administration nor Ang II/AT₁R-associated protein (ATRAP: Its activation enhances AT₁R internalization and specifically blocks its pathological effects) elimination alone resulted in progressive DN. Nevertheless, the combination of ATRAP elimination and Ang II infusion accelerated the progression of DN, which was characterized by obvious albuminuria, glomerular hypertrophy, loss of podocytes, expansion of mesangial, functional failure, and elevated AGT and AT₁R levels in the kidneys.⁶³ Clinical and animal studies have demonstrated increased AT₁R protein expression levels in diabetic mice,⁶⁴ and decreased AT₁R mRNA in the kidneys of diabetic spontaneously hypertensive rats (SHRs).⁶⁵ However, no significant decrease in AT₁R expression was seen in diabetic Wistar-Kyoto (WKY) rats.⁶⁵ The kidney AT₁R mRNA levels are significantly reduced in individuals with DN.^66–68 In eight samples of human DN, the AT₁R mRNA levels were substantially lower.⁶⁶ Another study found that non-diabetic participants had greater AT₁R mRNA levels than diabetic ones, although the difference was not statistically significant.⁶⁹ Ma et al., evaluated the levels of AT₁R in two groups of DN individuals: one group had just ARB treatment while the other group did not receive any RAS inhibitors. The levels of AT₁R protein rose in the initial phases of DN, but dropped in the late phase.⁶⁷ In this study, following treating individuals with ARBs (valsartan, losartan, irbesartan, olmesartan, and telmisartan), the levels of protein expression of AT₁R decreased in the tubular interstitial and glomeruli.⁶⁷ Valsartan inhibited the Notch pathway in diabetic mice's glomeruli, which reduced podocyte destruction.⁷⁰ Irbesartan inhibited DN-related metabolic abnormalities, podocyte damage, and renal impairment in db/db mice via targeting the RANKL-RANK-NF-κB cascade.⁷¹ In STZ-induced diabetic mice, the levels of ACE-2 and Ang1-7/Mas receptor (MasR) are drastically reduced, resulting in renal hypertrophy, tissue damage, and apoptosis via increased activation of ERK1/2, p38 MAPK, and JNK protein expression. Olmesartan therapy greatly lowers the phosphorylation of ERK1/2, p38 MAPK, and JNK. This may be because ACE-2 and Ang1-7/MasR are overexpressed. Thus, olmesartan improves STZ-induced DN via regulating the AT₁R/MAPK pathway.⁵¹

In diabetes, ROS perform a vital role in triggering the activity of Ang-II in renal cells. NADPH oxidase is the primary source of ROS formation, which causes tissue damage and results in DN through a variety of processes.⁷² AT₁R blockers’ beneficial impacts in DN are mostly due to reduced nitrosative and oxidative stress.^73,74 In STZ-induced diabetic mice, telmisartan diminishes fibrosis and oxidative stress through peroxisome proliferator activator (PPAR)-γ and olmesartan reduces the protein levels of gp91-phox, a NADPH oxidase component, superoxide radical, and 3-nitrotyrosine.^51,74 AT₁R stimulation exerts a critical role in the development of microalbuminuria to macroalbuminuria.^75,76 Olmesartan substantially lowered proteinuria levels in DN through improving glomerular porosity.^77–79 Some studies emphasize on the combination of mineralocorticoid receptor antagonists (MARs) with ARBs and ACEIs to reduce albuminuria and delay renal function decline (slower decline in eGFR) in patients with DN.^80,81 Diabetes patients have higher levels of TGF-β levels in their mesangial, glomerular, and endothelial cells.^82,83 Blocking TGF-β can inhibit fibrosis. Ang-II and high glucose levels promote the formation of collagen via TGF-β. Diabetics have higher levels of TGF-β in mesangial and endothelial cells in the glomeruli.^82,83 Valsartan decreased fibrosis and oxidative stress in mesangial and epithelial cells cultivated in high glucose environments through decreasing TGF-β levels.^84,85 In type 2 diabetics, candesartan reduced albuminuria by 60%. In type 2 diabetics, the combination of candesartan with an ACEI (dual blockade) resulted in a 25–35% reduction in albuminuria compared to ACEI alone.⁸⁶

Valsartan in STZ-induced diabetic rats decreased Ang II, ANGPTL2, TLR4, and integrin expression and improved albuminuria, blood pressure, urinary biomarkers, and fibrotic and apoptotic markers.⁸⁷ Researchers looked at AT₁R levels in two groups of DN patients: one group only got ARB medicine, and the other group did not get any RAS inhibitors. They found that AT₁R protein levels went up in the early stages of DN but went down in the later stages.⁶⁷ Lower levels of AT₁R in the kidneys of people with DN suggest that the balance between AT₁R and AT₂R -mediated cell signaling may influence DN progression.⁸⁸

Smad1 is an essential molecule that directly regulates the transcription of type IV collagen (Col4) in vitro, Col4 is a prominent factor in the enhanced ECM in DN. Diabetic rats show increased glomerular expression and urine excretion of Smad1, as well as mesangial expansion.⁸⁹ Smad1 and albumin in the urine were examined 4 weeks after injection of STZ rats or 6 weeks of diabetes in db/db mice. The renal pathology of the rats was examined after a duration of 20 weeks, whereas the mice were examined after 12 weeks. Urinary Smad1 of diabetic rats at 4 weeks showed a strong correlation with mesangial matrix expansion at 24 weeks, although albuminuria had a lesser correlation. Olmesartan therapy for 20 weeks relieved glomerulosclerosis and dramatically decreased urine Smad1. Significant correlations between 6-week urine Smad1 and 18-week mesangial expansion were also seen in db/db mice. On the other hand, control diabetic rats and mice did not exhibit any alteration in urine Smad1. The findings suggest that urinary Smad1 may serve as a new indicator for predicting the development of morphological alterations in the future and may be used to assess the impact of ARBs in DN.⁸⁹

Administration of olmesartan to diabetic rats for 20 weeks resulted in a decrease in albuminuria and hyperfiltration, without impacting blood pressure. Additionally, it suppressed the expansion of the mesangial matrix and the expression of Col4 and smooth muscle alpha actin, as compared to rats who did not receive treatment. Olmesartan suppressed the upregulation of Smad1, phospho-Smad1, and phospho-Src. Olmesartan prevented the Ang II-induced rise in Col4 production and the upregulation of phosphor-Src and phospho-Smad1 in cultured mesangial cells.⁹⁰ In addition, the phosphorylation of Smad1 was decreased by PP2, which is an inhibitor of Src tyrosine kinase, as well as by using dominant negative Src. Moreover, addition of small-interfering RNA against Src significantly reduced the phosphorylation of Smad1 and synthesis of Col4. In addition, the introduction of small-interfering RNA targeting Src resulted in a considerable decrease in the phosphorylation of Smad1 and the production of Col4. Collectively, Ang II can control the progression of mesangial matrix expansion in the first stage of DN via the involvement of Src and Smad1.⁹⁰

Ang II type 2 receptor in diabetic nephropathy

AT₂R activation inhibits cell proliferation and differentiation, neutralizing most of AT₁R actions. It also promotes the synthesis of NO, kinins (bradykinin, kallikrein), and cyclic guanosine 3'5-monophosphate (cGMP), which causes blood vessels to dilate and eventually lowers blood pressure.^11,91 AT₂R stimulation opposes the actions of renal AT₁R by increasing intrarenal NO generation, promoting natriuresis, and suppressing cell proliferation and matrix formation.^88,92 The AT₂R is extensively expressed in the fetal kidney, although it declines significantly throughout the neonatal stage. The adult kidney produces it in the proximal tubule cells, glomerular endothelium, mesangial cells, afferent arteriole, and interstitial cells.⁹³ AT₂R agonists are important parts of DN treatment plans because they increase NO and cGMP production and have antifibrotic, antiapoptotic, antioxidant, anti-inflammatory, antihypertrophic, and vasodilatory effects.⁵⁴ Combining C21 (an AT₂R agonist) with telmisartan reduced the activation of NF-κB-mediated inflammatory cascades and the generation of inflammatory agents like IL6, TNF-α, MCP1, and VCAM-1. They also improve lipid and carbohydrate metabolic indices, renal function, kidney morphology and microarchitectural aspects, and hemodynamic problems in T2D.⁹¹ In diabetes, insulin-like growth factor-1 (IGF-1) and insulin upregulate AT₂R, while Ang-Ⅱ downregulates it. Low expression of AT₂R in diabetes has been demonstrated by immunohistochemistry (IHC).⁷⁴ Early stages of diabetes show decreased expression of AT₂R in glomeruli and other kidney parts without changes in glomerular mRNA expression of AGT, renin, and ACE.⁹⁴ Compared to wild-type (WT) diabetic mice, AT₂R knockout diabetic mice had more ECM proteins, tubular apoptosis, and kidney hypertrophy.⁹⁵ C21 decreased macrophage infiltration, albuminuria, TNF-α expression, and fibrosis in DN.⁹⁶ In diabetic ApoE-deficient mice, C21 therapy decreased cystatin C levels, albuminuria, mesangial enlargement, and glomerulosclerosis. Furthermore, C21 suppressed oxidative stress, inflammatory, and profibrotic signalling, along with reduced ECM synthesis, and hence inhibited the progression of DKD.⁹⁷ After 4 weeks of diabetes, AT₂R knockout (AT₂RKO) mice had bigger kidneys, more tubular apoptosis, more ECM protein buildup, and a higher GFR than WT mice after 4 weeks of diabetes. In renal proximal tubules (RPTs) of AT2RKO mice, renal oxidative stress (heme oxygenase 1 (HO-1) gene expression and ROS production) as well as Ang, AT1R and ACE expressions were increased, while ACE2 expression was decreased.⁹⁵ When comparing diabetic Apoe-KO (apolipoprotein E knockout) mice to control Apoe-KO mice, AT₂R blockers reversed the higher aortic mRNA levels of AT₂R expression.⁹⁸

Angiotensin converting enzyme in diabetic nephropathy

ACE acts as an essential repressor enzyme that cleaves 2 amino acid residues from the C-terminal part of Ang I to produce Ang II, resulting in vasoconstriction. It also degrading the vasodilator Ang 1-7.⁹⁹ People with T2DM who have nephropathy showed higher renal and serum ACE values than people without nephropathy.^100–103 In 155 humans, ACE concentrations in people with DN were considerably greater than controls or people with T2DM. This suggests that ACE values may be a potential diagnostic for DN progression.¹⁰⁴ Ramipril reduced renal damage and proteinuria in Zucker diabetic fatty (ZDF) rats by reducing the elevation of Klotho and renal fibroblast growth factor levels.¹⁰⁵ Compared to the placebo, taking captopril for three years cut the risk of a double creatinine level and DKD-related death, dialysis, and transplantation by almost half (50%) in people with T1DM who also had DKD.¹⁰⁶The use of lisinopril for DKD individuals for two months inhibits glomerular and tubular injury and dysfunction, which is shown by a reduction in urine liver fatty acid-binding protein (U-LFABP) and albuminuria.¹⁰⁷ ACEIs contribute to maintaining the mRNA levels of nephrin (a slit-diaphragm protein) that is decreased in diabetes. This shows that RAS influences proteinuria in DN, possibly by reducing diabetes-induced alterations in nephrin production.^108,109 ACEIs decreased the progression from microalbuminuria to macroalbuminuria by approximately 55% and raised the rate of regression from microalbuminuria to normoalbuminuria by nearly 3.4 times.¹¹⁰ Lisinopril improves DN by suppressing renal MCP-1, which increases monocyte migration and differentiation into macrophages, enhancing tubule interstitial fibrosis and ECMsynthesis.¹¹¹ ACEIs enhances insulin sensitivity through inhibiting Ang II synthesis and/or boosting local and systemic bradykinin levels.¹¹² ACEIs lowers insulin resistance, which reduces insulin resistance^113,114 via raising Ang1-7 concentrations in tissues and plasma.¹¹⁵ The MasR antagonist (A-779) prevented the insulin-induced glucose uptake in rat skeletal muscle that captopril improved in vivo.¹¹⁶ In diabetic rats, enalapril medication reduced glomerular capillary hypertension, evaded glomerular structural damage, and proteinuria.¹⁰³

Angiotensin converting enzyme-2 in diabetic nephropathy

ACE-2, an ACE homolog and a component of the RAS,^1,2 can be found mainly in the intrarenal endothelium.¹¹⁷ ACE2 in the vessels and epithelium of renal tubules is a membrane-bound enzyme that is detected in soluble form in plasma and also in organs like the liver, heart, brain, kidney, and blood vessels.⁵⁰ ACE2 breaks down Ang II to Ang 1-7 and changes Ang I to Ang 1-9, which can then be transformed to Ang 1-7 through ACE, restricting Ang II generation.¹¹⁸ ACE2 is known as a classical RAS negative regulator by degrading Ang II.¹¹⁹ Ang 1-7, which results from the cleavage of Ang II by ACE2 through binding to the MasR, has anti-fibrotic, anti-inflammatory, and vasodilatory properties, thereby opposing the deleterious consequences generated by elevated amounts of Ang II.¹¹⁹ ACE2 appears to serve a protective function in the diabetic kidney and is a significant predictor of DN.¹²⁰ T2D patients with DN have decreased glomerular and renal tubular ACE2 levels.⁴⁵ Diabetic patients have considerably higher enzyme activity and protein expression of ACE2, which has a major impact on the pathogenesis of DN.¹²¹ In the diabetic kidney, ACE2 downregulation induces Ang II formation in the glomeruli and proximal tubules, which damages the glomeruli and albuminuria.¹²²

Diabetic renal transplant patients also excreted more urine ACE2 protein than non-diabetics.^34,121 Urinary ACE2 was considerably raised in non-diabetic renal disorders, but greatly enhanced in diabetes.¹²¹ Decreased levels of glomerular ACE2, together with elevated levels of ACE, have been identified in human T2D and db/db mouse models, leading to increased Ang Ang II formation and its detrimental implications.^12,118 Researchers have found that both genetic deletion and pharmacological blockade of ACE2 enhance albuminuria and induce glomerular damage.¹²² ACE2 expression in podocytes leads to albuminuria via inhibiting Ang II formation in the glomerulus and enhancing Ang II-induced glomerular permeability.^118,122 A direct relationship exists between the extent of proteinuria and urinary ACE2 mRNA expression, However, it remains unclear where exactly the changes in ACE and ACE2 occur inside the nephron.¹²² When hrACE2 is given to male Akita mice, which are used as a model for T1D, it decreases mild hypertension, albuminuria, plasma Ang II concentration, nicotinamide adenine dinucleotide phosphate oxidase stimulation, mesangial matrix expansion, glomerular hypertrophy, and elevated Ang 1-7 levels. These effects could impede the DN's progression.¹²³ The deficiency of ACE2 is associated with increased atherogenesis, which may be due to the decrease in soluble ACE2, which has a protective effect against the development of atherosclerosis. Elevating soluble ACE2 levels in diabetic mice, either by administering a recombinant protein or via a DNA minicircle, provides protection against heightened atherosclerosis in the arterial wall and reduces albuminuria. This increase in circulating soluble ACE2 can be used as a strategy to reduce vascular damage and dysfunction in diabetes.¹²⁴ Although ACE2 is confined to the cell membrane, it may be shed to produce a soluble form of the enzyme. This soluble form is often seen in the urine of individuals with diabetes. This process is facilitated through metalloproteinase-17 (ADAM17). Hyperglycemia and Ang II enhance the activity of ADAM17, which can underpin increased levels of soluble ACE2 in the setting of diabetes. Ang II and hyperglycemia boost ADAM17 activity, which can lead to an elevated level of soluble ACE2 in diabetes.¹¹⁹ Olmesartan, an AT₁R blocker, dramatically raised urine ACE2 amounts regardless of plasma aldosterone amounts and blood pressure, while decreasing urinary liver-type fatty acid binding protein (L-FABP), plasma aldosterone concentrations, and albuminuria.¹²⁵ In vitro, ACE2 inhibited excessive glucose-mediated tubular epithelial to mesenchymal cell transition (EMT), as seen by enhanced α SMA levels and decreased E cadherin levels. In human renal proximal tubular epithelial cells (HRPTEpiCs), ACE2 reduced EMT through decreasing Arkadia and increasing SMAD family member 7 (Smad7) protein levels, subsequently causing TGF-β/Smad pathway suppression. ACE2 protects the kidney against DN through inhibition of Arkadia-mediated Smad7 breakdown and improving TGF β/Smad-induced EMT in HRPTEpiCs treated with high glucose levels.¹²⁶ ACE2 upregulation in DN substantially inhibited Ang II-mediated oxidative stress and glomerular mesangial cells expansion, which subsequently lowered renal ECM buildup.¹¹⁷

ACE2 deletion in STZ-induced diabetic mice exacerbated glomerulosclerosis, tubular damage, interstitial fibrosis, podocyte death, and elevated serum creatinine concentrations.¹²⁷ Inhibiting ACE2 with MLN-4760 in STZ-induced diabetic mice and db/db mice enhanced fibronectin and collagen accumulation in the glomerulus and tubulointerstitial region, as well as mesangial matrix progression.^128,129 ACE2 protein and activity levels were also seen in the renal cortical area of both STZ-induced diabetic mice and db/db mice at the early onset of the illness, but no alteration in its mRNA content was found.¹³⁰ In one study, transgenic techniques using a nephrin promoter led to the overexpression of ACE2 in the podocytes of DN mice. These mice's glomeruli showed considerably greater amounts of ACE2 mRNA, protein, and activity than wild-type mice. At 4 weeks, WT diabetic mice had markedly higher albuminuria levels, but transgenic diabetic animals had no difference in albuminuria from wild-type nondiabetic mice. However, this impact was temporary, and after 16 weeks, both transgenic and nontransgenic diabetic mice exhibited a comparable incidence of proteinuria. Transgenic diabetes mice displayed a lower rise in the mesangial region, a reduced glomerular region, and a milder drop in nephrin production in comparison with WT diabetic mice. At 16 weeks, podocyte counts declined in WT diabetes mice but remained unaltered in transgenic diabetic mice. Transgenic diabetic mice had considerably lower TGF-β1 expression in their renal cortex compared with wild-type diabetic mice after 8 weeks. Therefore, podocyte-specific expression of human ACE2 temporarily retards DN progression.¹⁰⁹

Ang-II and high glucose levels promote the formation of collagen via TGF-β. Diabetics have higher levels of TGF-β in mesangial and endothelial cells in the glomeruli.^82,83 The diminished expression of ACE2 in diabetic kidneys demonstrates ACE2's rolein DN. A study was conducted to investigate the protective impacts of overexpression of ACE2, ACEIs, or both on DN. The Ad-green fluorescent protein (GFP) group showed higher renal superoxide dismutase activity, downregulated TGF-β1, collagen IV protein expression, vascular endothelial growth factor (VEGF), and reduced urinary albumin, creatinine clearance, glomeruli sclerosis, and renal malondialdehyde amount compared to the Ad-ACE2 group. In summary, ACE2 has reno-protective effects akin to those of ACEI therapy.¹¹⁷ Diabetes-associated albuminuria was exacerbated in MLN-4760-treated diabetic mice as well as in ACE2 KO animals. Nevertheless, fibrogenesis, renal hypertrophy, and hyperfiltration diminished in diabetic mice ACE2 KO.¹²⁰ In diabetic c57Bl6 mice, plasma ACE2 activity rose more than double, while the use of perindopril reduced it by approximately 75–80% in diabetic and normal c57Bl6 mice. In control mice, MLN-4760 exhibited no discernible impact on cortical ACE2 activity, but it lowered its activity in diabetic mice to levels seen in untreated control mice. MLN-4760 significantly lowered cortical concentrations of Ang 1-7 in both diabetic and control mice. In renal or plasma samples from ACE2 KO mice, there was no discernible ACE2 activity or gene expression.¹³¹ Diabetic ACE2-KO mice demonstrated a quicker start and severe development of albuminuria compared to WT mice. ACE2-KO diabetic mice had higher levels of serum urea nitrogen and creatinine, as well as tubular/glomerular injury, than WT mice. In ACE2-KO mice, the breakdown of nephrin, which is associated with albuminuria, decreased more quickly and severely, while the expression of VEGF increased more strongly. In ACE2-KO mice, olemesartan considerably, but not completely, improved the morphological and functional degradation of DN. These findings imply that ACE2 may provide protection against both tubulointerstitial and glomerular damage in the progression of DN by inhibiting Ang II-mediated AT₁R signaling.¹²⁷ Minicircle ACE2 significantly increased plasma ACE2 protein in STZ-diabetic rats, leading to a more than 100-fold increase in serum ACE2 activity. Nevertheless, when compared to untreated diabetic mice, minicircle ACE2 had no effect on urine ACE2 activity. As non-diabetic controls, Minicircle ACE2-untreated and treated diabetic mice had identical increases in albuminuria, glomerular mesangial enlargement, glomerular cell proliferation, glomerular size, and GFR.¹³²

Angiotensin1-7 in diabetic nephropathy

The production of Ang 1-7 is caused by the breakdown of Ang II by ACE2 and also comes directly from Ang I through NEP and.^133,134 Ang 1-7 via MasR causes vasodilation and thus has anti-inflammatory, antihypertensive, and anti-proliferative characteristics, functioning as a counter-regulator of Ang II's AT₁R-induced actions.⁵⁰ Compared with non-diabetic rats, STZ-induced diabetic rats revealed a substantial decrease in plasma, total kidney, and separated glomerular Ang 1-7 levels.¹³⁵ In Zucker Diabetic Fatty Rat (ZDF) rats, Ang 1-7 injection (100 ng/kg/min, 2 weeks) reduced systolic blood pressure, oxidative stress, IL-6, TNF-α, hypoxia-inducible factor-1α (HIF-1α), and NGAL, thereby inhibiting DKD.^136,137 Furthermore, Ang1-7 preserved the kidney of db/db mice from DKD by decreasing oxidative stress, inflammation, and lipotoxicity.¹³⁸ Intrarenal administration of Ang 1-7 into T1DM rats enhanced urinary sodium excretion, decreased proximal tubular reabsorption, and adjusted GFR.³⁸ Ang1-7 treatment improved STZ-induced DKD more than valsartan, lowering oxidative stress and attenuating TGF-β and VEGF-mediated pathogenic pathways.¹³⁹ Ang 1-7 inhibits the activation of Ang-II MAPK and MAPK p38 caused by high glucose (linked to nephron injury and renal cell fibrosis and hypertrophy). This reduces the expression of p38MAPK and preserves the nephron.^140,141

Cyclic (c) Ang1-7, in which the amino acids Tyr4 and Pro7 were replaced with D, L lanthionine (dAla-S-Ala), has robust reno-protective benefits in BTBR ob/ob mice.¹⁴² cAng1-7 inhibits glomerular fibronectin, mesangial matrix expansion, and macrophage/ monocyte aggregation in BTBR ob/ob mice as effectively as lisinopril.¹⁴² Combining cAng 1-7 with lisinopril was shown to have an additional antiproteinuric impact, improve podocyte protein conservation, and increase capillary density.¹⁴² Dysfunctional endothelial cells and capillary absence influence the glomerular filtration barrier's permeability, resulting in albuminuria in DN. In mice with diabetes, cAng1-7 prevents endothelium injury in the glomeruli.¹⁴² When Ang1-7 was given subcutaneously to Zucker murine diabetic rats, there was a decrease in proinflammatory markers, ECM, and fibrosis. In one research, Ang II levels were significantly higher in the group that received Ang 1-7 than in the control group, indicating that Ang 1-7 had protective benefits despite the rise in local Ang II.¹³⁷ By reducing NADPH oxidase activity and suppressing ROS generation, Ang 1-7 positively impacts DN in db/db miceon in db/db mice.¹⁴³ In diabetic rats, Ang1-7 and/or (AVE-0991) (MasR agonist) diminish albuminuria, and aberrant vascular reactions to endothelin-1, norepinephrine, and Ang II. These findings suggest that Ang1-7 can be a protective factor in diabetes.¹⁴⁴ Genetic elimination of the MasR has been found to promote hyperfiltration and deteriorating renal disease, while Ang 1-7 can improve DN.^137,138 Following four weeks of STZ injection, the use of Ang 1-7 and Ang 1-7 + A-779 were initiated. Ang 1-7 reduced STZ-induced nephropathy via lowering renal collagen levels, and proteinuria, and enhancing endothelial abilities without stopping tubular injury.¹³⁶ Ang 1-7 reduced blood urea nitrogen (BUN) and dyslipidemia in diabetic rats. But, creatinine clearance, serum creatinine, and kidney weight/body weight (%) were not impacted by Ang 1-7.¹³⁶ Early DN is characterized by a boost in AT₁R renal expression. In DN patients, the use of valsartan decreased and increased the expression of AT₁R and MasR (respectively).⁶⁷ After 12 weeks of inducing diabetes, the rats were divided into several groups based on their treatment for 4 weeks. The groups included: no therapy, low dosage, medium dose, and high dose. The subgroups consisted of Ang 1-7, valsartan, high-dose Ang 1-7 + Valsartan, and A779. Ang 1-7 improved kidney function, decreased oxidative stress, prevented glomeruli sclerosis, and inhibited cell proliferation. It further decreased the levels of TGF-β, collagen IV, VEGF, and NOX4, VEGF. Large-dose Ang 1-7 alone and in conjunction with valsartan were more effective than valsartan alone, but the combination had no significant synergistic impact compared to Ang 1-7 alone. Therefore, Ang 1-7 improved STZ-caused diabetic kidney damage. Ang 1-7 inhibited the development of DN in a dose-dependent manner, as evidenced by enhanced creatinine clearance and a reduced proportion of kidney weight to body weight, 24-h urine volume, 24-h albuminuria, and plasma creatinine concentrations.⁶⁷

Mas receptor in diabetic nephropathy

Ang1-7 by binding to MasR inhibits the effects of AT₁R by activating the Ang1-7/ACE2/MasR axis, which causes vasodilatation, increases diuresis and natriuresis, and lowers blood pressure. Deletion of MasR increased GFR, microalbuminuria, tubulointerstitial, and glomerular fibrosis along with the boost in the levels of AT₁R and TGF-β mRNA.¹⁴⁵ STZ-caused T1DM mice reduced MasR expression in the kidney, which was effectively normalized through telmisartan therapy for DKD.⁷⁴ AVE 0991 reduced diabetes-related abnormal vascular response to Ang II, endothelin-1, norepinephrine, and histamine in the isolated kidney artery.¹⁴⁶ AVE 0991 improved renal function by reducing antioxidant enzymes, apoptotic agents, and inflammatory factors in apolipoprotein E (ApoE) knockout mice.¹⁴⁷ After the treatment by constant Ang 1-7 vein injection for 6 weeks, renal function was found to be even worse than diabetic rats, and both TGF-β1 mRNA and protein levels were elevated in the STZ-induced diabetes with chronic Ang 1-7 (D + Ang 1-7) group compared with the diabetic rats. The real-time PCR result also showed an increase in ACE mRNA expression and decrease in ACE2 mRNA level in the D + Ang 1-7 group when compared with diabetic rats. The number of AT₁R increased in the Ang 1-7 -injected group, while the number of AT₂ and Mas receptors decreased. Thus, Exogenous Ang 1-7 injection did not ameliorate STZ- induced diabetic rat renal injury; on the contrary, it accelerated the progressive.¹⁴⁸

Conclusion

Hyperglycemia's excessive activation of the RAS, as well as the resulting changes in the expression of various components of both the ACE/Ang II/AT₁R and ACE2/Ang 1-7/MasR axes, play a critical role in the onset, development, and progression of DN. As a result, the first line of therapy for DN is RAS inhibition with ACEIs or ARBs, either alone or in combination. However, multiple preclinical and clinical investigations show that inhibiting RAS can only partly slow the course of DN and is unable to totally treat it.

Footnotes

Acknowledgments

The authors thank Behbahan Faculty of Medical Sciences for financial support (Grant # 402001).

Author contributions

All authors have made substantial contributions to the following: (1) the conception and design of the study, the acquisition of data (2) drafting the article or revising it critically for important intellectual content; (3) and final approval of the version to be submitted. The contributions of individual authors are as follows:

Farzaneh Karimi: conception and design of the study, the acquisition of data, validation, writing original draft, project administration.

Maryam Maleki: validation, writing original draft.

Ahmad Movahedpour: validation, writing original draft.

Mehdi Alizadeh: validation, draw the figure.

Ebrahim kharazinejad: validation, writing original draft.

Mohammad Sabaghan: validation, writing original draft.

All authors have read and approved the final manuscript. The corresponding author confirms the accuracy of the contributions and has obtained the necessary approvals from all authors.

Data availability

All data generated during this study are included in this published article.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical standards

This article does not contain any studies with human participants performed by any of the authors.

Funding

The author(s) declare that the Behbahan Faculty of Medical Science financially supported the present article (Grant # 402001).

ORCID iDs

Farzaneh Karimi

Maryam Maleki

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Overview of the renin-angiotensin system in diabetic nephropathy

Abstract

Keywords

Introduction

Renin angiotensin system in the kidney

Renin in diabetic nephropathy

Angiotensinogen in diabetic nephropathy

Angiotensin II in diabetic nephropathy

Ang II type 1 receptor in diabetic nephropathy

Ang II type 2 receptor in diabetic nephropathy

Angiotensin converting enzyme in diabetic nephropathy

Angiotensin converting enzyme-2 in diabetic nephropathy

Angiotensin1-7 in diabetic nephropathy

Mas receptor in diabetic nephropathy

Conclusion

Footnotes

Acknowledgments

Author contributions

Data availability

Declaration of conflicting interests

Ethical standards

Funding

ORCID iDs

References