Irisin Ameliorates Renal Tubulointerstitial Fibrosis by Regulating the Smad4/β-Catenin Pathway in Diabetic Mice

Abstract

Background The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes. Methods The purpose of this article is to examine irisin’s function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-β1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices. Results In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and β-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/β-catenin signaling pathway. Conclusion The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/β-catenin pathway.

Potential role of irisin in lung diseases and advances in research

“…There is an inextricable relationship between irisin and fibrosis. It has a protective effect in hepatic fibrosis, renal fibrosis, pancreatic fibrosis, and cardiac fibrosis, and it may be a potential target for therapy (Ren et al, 2020;Pan et al, 2021;Armandi et al, 2022;Yang et al, 2023). In a mouse model of carbon tetrachloride-induced hepatic fibrosis, irisin appears to play a key role and can alleviate endoplasmic reticulum stress and hepatic fibrosis through inhibition of protein kinase RNA-like endoplasmic reticulum kinase-mediated destabilization of heterogeneous nuclear ribonucleoprotein A1 (Liao et al, 2021).…”

“…Irisin also reduces renal fibrosis. In-vivo and in-vitro studies on diabetic nephropathy have revealed that irisin attenuates epithelial-mesenchymal transition (EMT) and fibrosis as well as reduces renal injury by inhibiting the Smad/β-catenin pathway (Yang et al, 2023). Furthermore, irisin attenuates angiotensin II-induced and doxorubicin-induced cardiac fibrosis as well as cardiomyocyte hypertrophy (Chen et al, 2019;Pan et al, 2021).…”