Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-β and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.
RemuzziGBenigniARemuzziA. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest2006; 116: 288–296.
2.
IngelfingerJR. Aliskiren and dual therapy in type 2 diabetes mellitus. N Engl J Med2008; 358: 2503–2505.
3.
PriceDAPorterLEGordonM. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol1999; 10: 2382–2391.
4.
SkeggsTJrKahnJRLentzK. The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J Exp Med1957; 106: 439–453.
CohenNC. Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge. Chem Biol Drug Des2007; 70: 557–565.
7.
VillamilAChrysantSGCalhounD. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens2007; 25: 217–226.
8.
StantonAJensenCNussbergerJ. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertens2003; 42: 1137–1143.
9.
OparilSYarowsSAPatelS. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet2007; 370: 221–229.
10.
PilzBShagdarsurenEWellnerM. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertens2005; 46: 569–576.
11.
KellyDJZhangYMoeG. Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia2007; 50: 2398–2404.
12.
DahlofBDevereuxRBKjeldsenSE. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet2002; 359: 995–1003.
13.
KjeldsenSEJuliusSManciaG. VALUE Trial Investigators. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens2006; 24: 1405–1412.
14.
ScheenAJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. Meta-analysis of randomized clinical trials. Diabetes Metab2004; 30: 487–496.
15.
LuaTCarlssonPOLeungPS. Evidence of a local angiotensingenerating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia2004; 47: 240–248.
16.
ChuKYLauTCarlssonPO. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes2006; 55: 367–374.
17.
FuruhashiMUraNHigashiuraK. Blockade of the renin angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertens2003; 42: 76–81.
18.
YoshihikoHTakuyaIKaoruY. Effects of Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on hyperglycemia in streptozotocin-induced diabetic rats. Biol Pharm Bull2007; 30: 1015–1020.
19.
NyathaniHKSrirangamPJinuguVS. Renoprotective effects of combined aliskiren and valsartan in diabetic nephropathy in rats. Intl J Pharm Sci Rev Res2011; 6: 152–158.
20.
ArulmozhiDKVeeranjaneyluABodhankarSL. Neonatal streptozotocin induced rat model of type 2 diabetes mellitus: a glance. Ind J Pharmacol2004; 36: 217–221.
21.
MatsunoTSasakiHNakagawaK. Fas antigen expression and apoptosis in kidney allografts. Transplant Proc1997; 29: 177–178.
22.
WeirGCCloreEEZmachinskiCJ. Islet secretion in new experimental model of non-insulin dependent diabetes. Diab Metab Rev1981; 30: 590–594.
23.
DanielJR. β-cell in type 2 diabetes mellitus. Diabetes1991; 40: 116–180.
24.
MasielloPBrocaCGrossR. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes1998; 47: 224–229.
25.
KellyDJWilkinson-BerkaJLAllenTJ. A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR). Kid Intl1998; 154: 343–352.
26.
LakshmananAPThandavarayanRAWatanabeK. Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice. Mol Cell Endocrinol2012; 348: 104–111. Epub ahead of print 30July2011. DOI: 10.1016/j.mce.2011.07.041.
27.
O’BrienEBartonJNussbergerJ. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertens2007; 49: 276–284.
28.
ParvingHHPerssonFLewisJB. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med2008; 358: 2433–2446.
29.
RiccioniG. Aliskiren in the treatment of hypertension and organ damage. Cardiovasc Ther2011; 29: 77–87.
30.
PeñacarrilloVMJesúsPAraceliR. Effect of GLP-1 treatment on GLUT2 and GLUT4 expression in type 1 and type 2 rat diabetic models. Endocrine2001; 15: 241–248.
31.
HabibiJWhaley-ConnellAHaydenMR. Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat. Endocrinol2008; 149: 5643–5653.
32.
SchererPEBickelPEKotlerM. Cloning of cell-specific secreted and surface proteins by subtractive antibody screening. Nat Biotechnol1998; 16: 581–586.
33.
YamauchiTKamonJMinokoshiY. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med2002; 8: 1288–1295.
34.
LastraGHabibiJWhaley-ConnellAT. Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. Endocrinol2009; 150: 2561–2568.
35.
SnehalathaCMukeshBSimonM. Plasma adiponectin as an independent predictor of type 2 diabetes especially in Asian Indians. Diabetes Care2003; 26: 3226–3229.
36.
OkamotoYAritaMNishidaM. An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metabol Res2000; 32: 47–50.
37.
FiorentinoADCianchettiSCeliA. Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS. JRAAS2010; 11: 243–247.
38.
NakamakiSSatohHKudohA. Adiponectin reduces proteinuria in streptozotocin-induced diabetic Wistar rats. Exp Biol Med (Maywood)2011; 236: 614–620.
39.
De ZeeuwDRemuzziGParvingHH. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation2004; 110: 921–927.
40.
De ZeeuwDRemuzziGParvingHH. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kid Intl2004; 65: 2309–2320.
41.
AtkinsRCBrigantiEMLewisJB. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kid Dis2005; 45: 281–287.
42.
ParvingHH. Renoprotection in diabetes: genetic and non-genetic risk factors and treatment. Diabetologia1998; 41: 745–759.
43.
EijkelkampWBZhangZRemuzziG. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol2007; 18: 1540–1546.
44.
GrieveKABalazsNComperWD. Protein fragments in urine have been considerably underestimated by various protein assays. Clin Chem2001; 47: 1717–1719.
45.
KaysenGDonBR. Serum albumin concentration and chronic kidney disease. US Nephrol2010; 5: 20–27.
46.
RoySSenC KKobuchiH. Antioxidant regulation of phorbol ester-induced adhesion of human Jurkat T-cells to endothelial cells. Free Radic Biol Med1998; 25: 229–241.
47.
AllisonAE. Proteinuria and interstitial injury. Nephrol Dial Transplant2004; 19: 277–281
48.
PerssonFLewisJBLewisEJ. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol2011; 6: 1025–1031.
49.
ShafiqMMMenonDVVictorRG. Oral direct renin inhibition: premise, promise, and potential limitations of a new class of antihypertensive drug. Am J Med2008; 121: 265–271.
50.
AziziMMenardJBisseryA. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol2004; 15: 3126–3133.
51.
GradmanAHSchmiederRELinsRL. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation2005; 111: 1012–1018.
52.
OhBHMitchellJHerronJR. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol2007; 49: 1157–1163.
53.
SealeyJELaraghJH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens2007; 20: 587–597.
54.
SontaInoguchiTMatsumotoS. In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker. Biochem Biophys Res Commun2005; 330: 415–422.
55.
ChenHQingLiYu-qianBao. The protective effect of the RAS inhibitor on diabetic patients with nephropathy in the context of VEGF suppression. Acta Pharmacol Sin2009; 30: 242–250.
56.
HuangYNobleNAZhangJ. Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kid Intl2007; 72: 45–52.
JohnstonCIRisvanisJNaitohM. Mechanism of progression of renal disease—current hemodynamic concepts. J Hypertens1998; 16: S3–S7.
59.
AndersonS. Role of local and systemic angiotensin in diabetic renal disease. Kid Intl1997; 52: S107–S110.
60.
BrennerBM. Hemodynamically mediated glomerular injury and the progressive nature of kidney diseaseKid Intl1983; 23: 647–655.
61.
AdvaniAKellyDJAdvaniSL. Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. Proc Nat Acad Sci U S A2007; 104: 14448–14453.
62.
IzuharaYNangakuMInagiR. Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J Am Soc Nephrol2005; 16: 3631–3641.
DavidJ. Evaluation of renal function. Nephrology2005; 10: 133–176.
67.
FillerGWittIPriemF. Are cystatin c and b2-microglobulin better markers than serum creatinine for prediction of a normal glomerular filtration rate in pediatric subjects?Clin Chem1997; 43: 1997.
68.
KazamaJJKutsuwadaKAtakaK. Serum cystatin c reliably detects renal dysfunction in patients with various renal diseases. Nephron2002; 91: 13–20.
69.
WesthuyzenJ. Review: Cystatin c: a promising marker and predictor of impaired renal function. Annals Clin Lab Sci2006; 36: 387–394.
70.
TenstadORoaldABGrubbA. Renal handing of radiolabelled human cystatin c in the rat. Scand J Clin Lab Invest1996; 56: 409–414.
71.
FliserDRitzE. Serum cystatin c concentration as a marker of renal dysfunction in the elderly. Am J Kid Dis2001; 37: 79–83.
72.
WinchesterJFSalsbergJALevinNW. Beta-2 microglobulin in ESRD: an in-depth review. Adv Renal Replace Ther2003; 10: 279–309.
73.
LapsleyMPASansomCTMarlowFV. Beta2-glycoprotein- 1 (apolipoprotein H) excretion in chronic renal tubular disorders: comparison with other protein markers of tubular malfunction. J Clin Pathol1991; 44: 812–816.
74.
ByungWLSungHIMoonGC. The comparison of cystatin c and creatinine as an accurate serum marker in the prediction of type 2 diabetic nephropathy. Diab Res Clin Pract2007; 78: 428–434.
75.
JernbergTLindahlBJamesS. Cystatin c. A novel predictor of outcome in suspected or confirmed non-ST elevation acute coronary syndromes. Circulation2004; 110: 2342–2348.
