Chronic high-fat diet (HFD) consumption is linked to chronic kidney disease. Toll-like receptor 4 (TLR4) promotes pro-fibrotic and pro-inflammatory pathways in the kidney. It is directly inhibited by renal miR-874. trans-Chalcone has protective effects against HFD-related diseases. However, its effects on renal miR-874 and TLR4 expression in HFD-fed animals remain unexamined.
Aim
The current study examined the possible influences of trans-chalcone and HFD on the renal miR-874/TLR4 axis.
Methods
Male rats were divided into control, HFD, and HFD + trans-chalcone groups. They received Tween 80 in control, high-fat emulsion in HFD and HFD + trans-chalcone groups, and trans-chalcone in the HFD + trans-chalcone group. Fasting insulin resistance index (FIRI) was calculated, and real-time PCR was used to determine the expression levels of miR-874 and TLR4 in the kidneys.
Results
Chronic HFD feeding elevated FIRI levels. In contrast, co-treatment with trans-chalcone and HFD significantly reduced FIRI levels in the HFD + trans-chalcone group compared with the HFD group. Consumption of an HFD also significantly reduced miR-874 and increased TLR4 expression. These HFD-induced changes were inhibited by trans-chalcone. There were no significant differences in renal expression of miR-874 and TLR4 between the control and HFD + trans-chalcone groups.
Conclusion
Down-regulation of renal miR-874 may be responsible for elevated TLR4 mRNA levels during HFD feeding. Furthermore, miR-874 dysregulation may be linked to the development of HFD-related kidney disease. This study suggests that trans-chalcone is a potential therapeutic chalcone for protecting the kidney against the dysregulation of the miR-874/TLR4 pathway during HFD feeding.
Ale-EbrahimMRahmaniRFaryabiK, et al. (2022) Atheroprotective and hepatoprotective effects of trans-chalcone through modification of eNOS/AMPK/KLF-2 pathway and regulation of COX-2, Ang-II, and PDGF mRNA expression in NMRI mice fed HCD. Molecular Biology Reports49(5): 3433–3443.
2.
AmisiCA (2022) Markers of insulin resistance in polycystic ovary syndrome women: An update. World Journal of Diabetes13(3): 129–149.
3.
ConstantinescuTLunguCN (2021) Anticancer activity of natural and synthetic chalcones. International Journal of Molecular Sciences22(21): 11306.
4.
DuncanMHSinghBMWisePH, et al. (1995) A simple measure of insulin resistance. Lancet346(8967): 120–121.
5.
ForemanKJMarquezNDolgertA, et al. (2018) Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: Reference and alternative scenarios for 2016–40 for 195 countries and territories. The Lancet392(10159): 2052–2090.
6.
GeJZhangXLiuY, et al. (2024) miR-874-3p is identified as a biomarker for acute kidney injury and mediates disease development via targeting MSRB3. Nephron148(6): 426–436.
7.
GholamiHJeddiSZadeh-VakiliA, et al. (2017) Transient congenital hypothyroidism alters gene expression of glucose transporters and impairs glucose sensing apparatus in young and aged offspring rats. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology43(6): 2338–2352.
8.
GuoJLiJWeiH, et al. (2021) Maackiain protects the kidneys of type 2 diabetic rats via modulating the Nrf2/HO-1 and TLR4/NF-κB/caspase-3 pathways. Drug Design, Development and Therapy15(null): 4339–4358.
9.
JabbarZIrfanHMAlamgeer, et al. (2024) Trans-chalcone (1-3-diphenyl-2-propen-1-one) as a therapeutic candidate in joint inflammation via reduction of TNF-α, IL-1β, IL-6, and IL-17 in rodents: An in vivo study by RT-PCR and ELISA analysis. ACS Omega9(20): 22123–22135.
10.
Karimi-SalesEEbrahimi-KalanAAlipourMR (2019) Preventive effect of trans-chalcone on non-alcoholic steatohepatitis: Improvement of hepatic lipid metabolism. Biomedicine & Pharmacotherapy109: 1306–1312.
11.
Karimi-SalesEJeddiSEbrahimi-KalanA, et al. (2018) trans -Chalcone prevents insulin resistance and hepatic inflammation and also promotes hepatic cholesterol efflux in high-fat diet-fed rats: modulation of miR-34a-, miR-451-, and miR-33a-related pathways. Food & Function9(8): 4292–4298.
12.
KimJJSearsDD (2010) TLR4 and insulin resistance. Gastroenterology Research and Practice2010(1): 212563.
13.
LiLZhaoZXiaJ, et al. (2015) A long-term high-fat/high-sucrose diet promotes kidney lipid deposition and causes apoptosis and glomerular hypertrophy in Bama minipigs. PLoS ONE10(11): e0142884.
14.
LiNZhaoGXuM (2023) Kluyveromyces marxianus ameliorates high-fat-diet-induced kidney injury by affecting gut microbiota and TLR4/NF-κB pathway in a mouse model. Cellular Microbiology2023(1): 2822094.
15.
LiuPLiFXuX, et al. (2020) 1,25(OH)(2)D(3) Provides protection against diabetic kidney disease by downregulating the TLR4-MyD88-NF-κB pathway. Experimental and Molecular Pathology114: 104434.
16.
LivakKJSchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods25(4): 402–408.
17.
MukhadiSHullRMbitaZ, et al. (2015) The role of microRNAs in kidney disease. Non-Coding RNA1(3): 192–221.
18.
MullerCRLeiteAPOYokotaR, et al. (2019) Post-weaning exposure to high-fat diet induces kidney lipid accumulation and function impairment in adult rats. Frontiers in Nutrition6: 60.
19.
MunakarmiSGurauYShresthaJ, et al. (2024) trans-Chalcone ameliorates CCl4-induced acute liver injury by suppressing endoplasmic reticulum stress, oxidative stress and inflammation. Pathology – Research and Practice263: 155663.
20.
NajafianMEbrahim-HabibiAYaghmaeiP, et al. (2010) Core structure of flavonoids precursor as an antihyperglycemic and antihyperlipidemic agent: An in vivo study in rats. Acta Biochimica Polonica57(4): 553–560.
21.
NatesanVKimS-J (2025) Natural compounds in kidney disease: Therapeutic potential and drug development. Biomolecules & Therapeutics33(1): 39–53.
22.
PahwaRJialalI (2016) Hyperglycemia induces toll-like receptor activity through increased oxidative stress. Metabolic Syndrome and Related Disorders14(5): 239–241.
23.
PetersLJFFloegeJBiessenEAL, et al. (2020) MicroRNAs in chronic kidney disease: Four candidates for clinical application. International Journal of Molecular Sciences21(18): 6547.
24.
RochaSRibeiroDFernandesE, et al. (2020) A systematic review on anti-diabetic properties of chalcones. Current Medicinal Chemistry27(14): 2257–2321.
25.
RudrapalMKhanJDukhyilAAB, et al. (2021) Chalcone scaffolds, bioprecursors of flavonoids: Chemistry, bioactivities, and pharmacokinetics. Molecules26(23): 7177.
26.
SchroppelBHeJC (2006) Expression of toll-like receptors in the kidney: Their potential role beyond infection. Kidney International69(5): 785–787.
27.
SinghHSidhuSChopraK, et al. (2016) Hepatoprotective effect of trans-chalcone on experimentally induced hepatic injury in rats: Inhibition of hepatic inflammation and fibrosis. Canadian Journal of Physiology and Pharmacology94(8): 879–887.
28.
SouzaACTsujiTBaranovaIN, et al. (2015) TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression. Physiological Reports3(9). doi:10.14814/phy2.12558
29.
SpotoBPisanoAZoccaliC (2016) Insulin resistance in chronic kidney disease: A systematic review. American Journal of Physiology-Renal Physiology311(6): F1087–F1108.
30.
SunMHuangYLiF, et al. (2018) MicroRNA-874 inhibits TNF-α-induced remodeling in human fetal airway smooth muscle cells by targeting STAT3. Respiratory Physiology & Neurobiology251: 34–40.
31.
SunYGeXLiX, et al. (2020) High-fat diet promotes renal injury by inducing oxidative stress and mitochondrial dysfunction. Cell Death & Disease11(10): 914–914.
32.
SvenssonKSchnyderSCardelB, et al. (2016) Loss of renal tubular PGC-1α exacerbates diet-induced renal steatosis and age-related urinary sodium excretion in mice. PLoS ONE11(7): e0158716.
33.
TsarouhasKTsitsimpikouCHaliassosA, et al. (2011) Study of insulin resistance, TNF-α, total antioxidant capacity and lipid profile in patients with chronic heart failure under exercise. In Vivo (Athens, Greece)25(6): 1031–1037.
34.
XuHCarreroJJ (2017) Insulin resistance in chronic kidney disease. Nephrology22(S4): 31–34.
35.
YaoTZhaDGaoP, et al. (2018) miR-874 Alleviates renal injury and inflammatory response in diabetic nephropathy through targeting toll-like receptor-4. Journal of Cellular Physiology234(1): 871–879.
36.
YiuWHLinMTangSCW (2014) Toll-like receptor activation: From renal inflammation to fibrosis. Kidney International Supplements4(1): 20–25.
37.
ZhangBRameshGUematsuS, et al. (2008) TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. Journal of the American Society of Nephrology19(5): 923–932.
38.
ZhangMZhangBWangL, et al. (2015) Increased expressions of TLR4 and related proinflammatory signaling molecules in the renal tissues of obese mice induced by high-fat diet. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi31(9): 1170–1174.
39.
ZhangYWeiYLiX, et al. (2018) MicroRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway. Cell Death & Disease9(2): 30.
40.
ZhongYWuSYangY, et al. (2020) LIGHT Aggravates sepsis-associated acute kidney injury via TLR4-MyD88-NF-κB pathway. Journal of Cellular and Molecular Medicine24(20): 11936–11948.
41.
ZouYLiJLuC, et al. (2006) High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sciences79(11): 1100–1107.
