Naringenin Ameliorated Kidney Injury through Let-7a/TGFBR1 Signaling in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). However, the exact mechanism is not clearly understood. In this study, our results showed that 24 h urinary protein, kidney index, and glomerular area were decreased, while creatinine clearance ratio was increased in DN rats when the rats were treated with NAR 50 mg/d for 6 weeks. Mesangial cell (MMCs) proliferation was inhibited in the NAR group by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and the cell cycle analysis showed that cells stayed in G2 phase in NAR group. And NAR treatment attenuated the deposition of ECM in DN rats and MMCs. Moreover, our data showed that let-7a was downexpressed in both DN rats and MMCs under high glucose condition. Surprisingly, NAR affected the expressions of Col4 and FN through upregulating let-7a in MMCs. In addition, we found that let-7a negatively regulated the expression of transforming growth factor-β1 receptor 1 (TGFBR1), and TGFBR1 was required for the let-7a-mediated downregulation of TGF-β1/smad signaling. Interestingly, NAR inhibited TGF-β1/smads signaling activation by upregulating let-7a. Therefore, our findings indicated that NAR ameliorated kidney injury by regulating let-7a/TGFBR1 signaling.

Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases

“…miR-199a has also been reported to be involved in inflammation via modulating the activation of NF-κB by targeting Klotho in lupus nephritis [42]. Sun et al reported the increased level of serum miR-199b-5p in diabetic patients [43]. They also indicated that the inhibition of miR-199b ameliorated TGF-β1-induced EMT and renal fibrosis via targeting SIRT1 in diabetic nephropathy [43].…”

“…Sun et al reported the increased level of serum miR-199b-5p in diabetic patients [43]. They also indicated that the inhibition of miR-199b ameliorated TGF-β1-induced EMT and renal fibrosis via targeting SIRT1 in diabetic nephropathy [43]. Kang et al suggested that miR-199b-5p targets klotho, thereby promoting renal tubular injury in diabetic nephropathy [77].…”

MicroRNA let‐7a regulates angiogenesis by targeting TGFBR3 mRNA

“…Dysregulated angiogenesis is considered to be one of the fundamental mechanisms regulating initiation and development of many diseases, such as cancer, heart disease and inflammation . In this study we found that TGFBR3 is a novel target of let‐7a.…”

“…It has been recently shown that let‐7a, along with other miRNAs may favour the “Off” switch of tumour angiogenesis in a mouse model of breast tumour undergoing hormone therapy . Intriguingly, TGFBR1, a member of TGFβ family, identified as potential target of let‐7, was critical for endothelium inflammation and cell differentiation …”

Rhein‑8‑O‑β‑D‑glucopyranoside inhibited high glucose‑induced apoptosis of human mesangial cells by regulating the lincRNA ANRIL/let‑7a/TGF‑β1/Smad signaling pathway

“…However, the role and mechanism of lincRNA ANRIL in HG-induced HMC apoptosis and Rg treatment are still unknown to the best of the authors' knowledge. let-7a was downregulated in both rats with DN and mesangial cells in an HG condition, and could negatively regulate the expression of TGFβ receptor 1 (18). Katayama et al (19) reported that glucose could significantly regulate the expression of let-7a by affecting promoter activity.…”