Losartan Alleviates Renal Fibrosis and Inhibits Endothelial-to-Mesenchymal Transition (EMT) Under High-Fat Diet-Induced Hyperglycemia.

Yufeng Yao,Zheng Ye,Yong Li,Xiaofei Zeng,Lu Zhang,Xia Li

doi:10.3389/fphar.2018.01213

Abstract

The endothelial-to-mesenchymal transition (EMT) of glomerular vascular endothelial cells is considered to be pivotal in diabetic nephropathy (DN). The risk of DN can be decreased by losartan, but the potential molecular mechanism(s) are not fully understood. Extensive data show that the EMT occurs in proximal tubular endothelial cells resulting in an endothelial phenotype switch (fibrotic matrix accumulation), consequently enhancing the development of renal interstitial fibrosis. Here, we found that losartan significantly ameliorated DN-induced renal fibrosis progression via inhibition of the EMT in mice. In vivo experiments suggested that losartan significantly alleviated microalbuminuria and pathologic changes under high-fat diet-induced hyperglycemia. Immunohistochemistry indicated that losartan suppressed the EMT in glomeruli. In addition, losartan decreased oxidative stress damage and inhibited the transforming growth factor (TGF)-β1/Smad pathway. Furthermore, consistent changes were detected in vitro where losartan markedly inhibited the EMT and TGF-β1/Smad pathway induced by high glucose in glomerular endothelial cells. Together, these results suggested that losartan could alleviate the EMT in glomeruli via inhibition of oxidative stress damage and the TGF-β1/Smad signaling pathway under hyperglycemia.

Highlights

Diabetes mellitus is characterized by hyperglycemia caused by the impairment of insulin secretion, insulin resistance (IR), or both (Wild et al, 2004; Tsai et al, 2018)
These results indicate that hyperglycemia model was successfully induced by High-fat diet (HFD)
To study the role of losartan in glucose metabolism and obesity, we first determined the effect of losartan on body weight

Summary

Introduction

Diabetes mellitus is characterized by hyperglycemia caused by the impairment of insulin secretion, insulin resistance (IR), or both (Wild et al, 2004; Tsai et al, 2018). Excessive caloric intake (due to unhealthy lifestyle) increases the risk of development of type 2 diabetes mellitus (T2DM) (Mourad et al, 2013). High-fat diet (HFD) intake results in progressive lipid accumulation in liver and muscles that conducting to activation of inflammatory cytokines and IR (Brownlee, 2005; Mourad et al, 2013). IR in T2DM and metabolic stress (mainly hyperglycemia and hyperlipidemia) acts as major risk factor for diabetic diseases (Bai et al, 2016). These risk factors referred to as metabolic syndrome (Decleves et al, 2013). Metabolic syndrome is known to be associated with a dysregulation of catalytic activities or expression levels of the metabolic enzymes that play a pivotal role in synthesis and/or consumption of glucose, lipid, and proteins (Wei et al, 2018)

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