Apelin/APJ alleviates diabetic nephropathy by improving glomerular endothelial cells dysfunction via SIRT3‑KLF15

Huang,Mingcong; Chang,Jing; Liu,Yu; Yin,Jiming; Zeng,Xiangjun

doi:10.3892/mmr.2025.13487

Apelin/APJ alleviates diabetic nephropathy by improving glomerular endothelial cells dysfunction via SIRT3‑KLF15

Authors:
- Mingcong Huang
- Jing Chang
- Yu Liu
- Jiming Yin
- Xiangjun Zeng
View Affiliations

Affiliations: Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, P.R. China, Department of Physiology, Beijing You An Hospital, Capital Medical University, Beijing 100069, P.R. China, Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, P.R. China, Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, P.R. China
Published online on: March 7, 2025 https://doi.org/10.3892/mmr.2025.13487
Article Number: 122
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glomerular basement membrane (GBM) thickening, the earliest morphological change of diabetic nephropathy (DN), is related to glomerular endothelial cells (GECs) dysfunction which increase extracellular matrix (ECM) synthesizing. Apelin, the endogenous ligand for apelin/apelin receptor (APJ), is reported to alleviate endothelial cell dysfunction in DN. Therefore, it was hypothesized that apelin/APJ reduced GBM thickening by decreasing the synthesis of ECM in GECs. The results showed that apelin reduced glomerular fibrosis and GBM thickening by decreasing the expression of laminin and collagen IV in diabetic mice, which were cancelled following APJ knockout in GECs. Furthermore, apelin/APJ inhibited the synthesis of laminin and collagen IV in GECs by increasing the expression and activity of SIRT3, which promoted KLF15 deacetylation and translocation into nucleus. In conclusion, apelin/APJ reduced GBM thickening in diabetes mellitus by preventing laminin and collagen IV synthesizing via SIRT3‑KLF15 pathway in GECs.

View Figures

View References

1	Papadopoulou-Marketou N, Chrousos GP and Kanaka-Gantenbein C: Diabetic nephropathy in type 1 diabetes: A review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev. 33:28412017. View Article : Google Scholar : PubMed/NCBI
2	Alicic RZ, Rooney MT and Tuttle KR: Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 7:2032–2045. 2017. View Article : Google Scholar : PubMed/NCBI
3	Naylor RW, Morais MRPT and Lennon R: Complexities of the glomerular basement membrane. Nat Rev Nephrol. 17:112–127. 2021. View Article : Google Scholar : PubMed/NCBI
4	Marshall CB: Rethinking glomerular basement membrane thickening in diabetic nephropathy: Adaptive or pathogenic? Am J Physiol Renal Physiol. 311:F831–F843. 2016. View Article : Google Scholar : PubMed/NCBI
5	Tuleta I and Frangogiannis NG: Diabetic fibrosis. Biochim Biophys Acta Mol Basis. 1867:1660442021. View Article : Google Scholar : PubMed/NCBI
6	Petrazzuolo A, Sabiu G, Assi E, Maestroni A, Pastore I, Lunati ME, Montefusco L, Loretelli C, Rossi G, Ben Nasr M, et al: Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease. Pharmacol Res. 190:106710:2021.
7	St John PL and Abrahamson DR: Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and −11 chains. Kidney Int. 60:1037–1046. 2001. View Article : Google Scholar : PubMed/NCBI
8	Kriz W, Löwen J, Federico G, van den Born J, Gröne E and Gröne HJ: Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy. Am J Physiol Renal Physiol. 312:F1101–F1111. 2017. View Article : Google Scholar : PubMed/NCBI
9	Stefan G, Stancu S, Zugravu A, Petre N, Mandache E and Mircescu G: Histologic predictors of renal outcome in diabetic nephropathy: Beyond renal pathology society classification. Medicine (Baltimore). 98:e163332019. View Article : Google Scholar : PubMed/NCBI
10	Lenoir O, Jasiek M, Hénique C, Guyonnet L, Hartleben B, Bork T, Chipont A, Flosseau K, Bensaada I, Schmitt A, et al: Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy. 11:1130–1145. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wardle EN: How does hyperglycaemia predispose to diabetic nephropathy? QJM. 89:943–951. 1996. View Article : Google Scholar : PubMed/NCBI
12	DeFronzo RA, Reeves WB and Awad AS: Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 17:319–334. 2021. View Article : Google Scholar : PubMed/NCBI
13	Eringa EC, Serne EH, Meijer RI, Schalkwijk CG, Houben AJ, Stehouwer CD, Smulders YM and van Hinsbergh VW: Endothelial dysfunction in (pre) diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes. Rev Endocr Metab Disord. 14:39–48. 2013. View Article : Google Scholar : PubMed/NCBI
14	El Husseny MW, Mamdouh M, Shaban S, Ibrahim Abushouk A, Zaki MM, Ahmed OM and Abdel-Daim MM: Adipokines: Potential therapeutic targets for vascular dysfunction in type II Diabetes mellitus and obesity. J Diabetes Res. 2017:80959262017. View Article : Google Scholar : PubMed/NCBI
15	Kim S, Kim S, Hwang AR, Choi HC, Lee JY and Woo CH: Apelin-13 inhibits methylglyoxal-induced unfolded protein responses and endothelial dysfunction via regulating AMPK pathway. Int J Mol Sci. 21:40692020. View Article : Google Scholar : PubMed/NCBI
16	Cheng J, Luo X, Huang Z and Chen L: Apelin/APJ system: A potential therapeutic target for endothelial dysfunction-related diseases. J Cell Physiol. 234:12149–12160. 2019. View Article : Google Scholar : PubMed/NCBI
17	Mariappan MM: Signaling mechanisms in the regulation of renal matrix metabolism in diabetes. Exp Diabetes Res. 2012:7498122012. View Article : Google Scholar : PubMed/NCBI
18	Ni T, Lin N, Huang X, Lu W, Sun Z, Zhang J, Lin H, Chi J and Guo H: Icariin ameliorates diabetic cardiomyopathy through apelin/sirt3 signalling to improve mitochondrial dysfunction. Front Pharmacol. 11:2562020. View Article : Google Scholar : PubMed/NCBI
19	Guan YM, Diao ZL, Huang HD, Zheng JF, Zhang QD, Wang LY and Liu WH: Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria. Amino Acids. 53:1229–1240. 2021. View Article : Google Scholar : PubMed/NCBI
20	Li N, Zhang J, Yan X, Zhang C, Liu H, Shan X, Li J, Yang Y, Huang C, Zhang P, et al: SIRT3-KLF15 signaling ameliorates kidney injury induced by hypertension. Oncotarget. 8:39592–39604. 2017. View Article : Google Scholar : PubMed/NCBI
21	Rane MJ, Zhao Y and Cai L: Krϋppel-like factors (KLFs) in renal physiology and disease. EBioMedicine. 40:743–750. 2019. View Article : Google Scholar : PubMed/NCBI
22	Gao X, Huang L, Grosjean F, Esposito V, Wu J, Fu L, Hu H, Tan J, He C, Gray S, et al: Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats: A role for KLF15. Kidney Int. 79:987–996. 2011. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, Ferrario F, Fogo AB, Haas M, de Heer E, et al: Renal pathology society. pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 21:556–563. 2010. View Article : Google Scholar : PubMed/NCBI
25	Wang Y, Zhang R, Shen H, Kong J and Lv X: Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM. Biosci Rep. 39:BSR201903172019. View Article : Google Scholar : PubMed/NCBI
26	Yin J, Wang Y, Chang J, Li B, Zhang J, Liu Y, Lai S, Jiang Y, Li H and Zeng X: Apelin inhibited epithelial-mesenchymal transition of podocytes in diabetic mice through downregulating immunoproteasome subunits β5i. Cell Death Dis. 9:10312018. View Article : Google Scholar : PubMed/NCBI
27	Abrahamson DR: Role of the podocyte (and glomerular endothelium) in building the GBM. Semin Nephrol. 32:342–349. 2012. View Article : Google Scholar : PubMed/NCBI
28	Lennon R, Byron A, Humphries JD, Randles MJ, Carisey A, Murphy S, Knight D, Brenchley PE, Zent R and Humphries MJ: Global analysis reveals the complexity of the human glomerular extracellular matrix. J Am Soc Nephrol. 25:939–951. 2014. View Article : Google Scholar : PubMed/NCBI
29	Miner JH: Type IV collagen and diabetic kidney disease. Nat Rev Nephrol. 16:3–4. 2020. View Article : Google Scholar : PubMed/NCBI
30	Seo K, Parikh VN and Ashley EA: Stretch-induced biased signaling in angiotensin ii type 1 and apelin receptors for the mediation of cardiac contractility and hypertrophy. Front Physiol. 11:1812020. View Article : Google Scholar : PubMed/NCBI
31	Eleftheriadis T, Antoniadi G, Pissas G, Liakopoulos V and Stefanidis I: The renal endothelium in diabetic nephropathy. Ren Fail. 35:592–599. 2013. View Article : Google Scholar : PubMed/NCBI
32	Swärd P and Rippe B: Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability. Acta Physiol (Oxf). 204:294–307. 2012. View Article : Google Scholar : PubMed/NCBI
33	Jaimes EA, Hua P, Tian RX and Raij L: Human glomerular endothelium: Interplay among glucose, free fatty acids, angiotensin II, and oxidative stress. Am J Physiol Renal Physiol. 298:F125–F132. 2010. View Article : Google Scholar : PubMed/NCBI
34	Li N, Ma X, Ban T, Xu S, Ma Y, Ason B and Hu LA: Loss of APJ mediated β-arrestin signalling improves high-fat diet induced metabolic dysfunction but does not alter cardiac function in mice. Biochem J. 477:3313–3327. 2010. View Article : Google Scholar : PubMed/NCBI