miR-98-5p Alleviated Epithelial-to-Mesenchymal Transition and Renal Fibrosis via Targeting Hmga2 in Diabetic Nephropathy

Abstract

Recently, microRNAs have been recognized as crucial regulators of diabetic nephropathy (DN) development. Epithelial-to-mesenchymal transition (EMT) can play a significant role in tubulointerstitial fibrosis, and it is a hallmark of diabetic nephropathy progression. Nevertheless, the function of miR-98-5p in the modulation of EMT and renal fibrosis during DN remains barely investigated. Hence, identifying the mechanisms of miR-98-5p in regulating EMT and fibrosis is of huge significance. In our present research, decreased miR-98-5p was demonstrated in db/db mice and mice mesangial cells treated with the high dose of glucose. Meanwhile, activated EMT and increased fibrosis was accompanied with the decrease of miR-98-5p in vitro and in vivo. Additionally, to further find out the roles of miR-98-5p in DN development, overexpression of miR-98-5p was applied. Firstly, in vivo investigation exhibited that elevation of miR-98-5p restrained proteinuria, serum creatinine, BUN, the EMT process, and fibrosis. Furthermore, high glucose was able to promote mice mesangial cell proliferation, EMT process, and induced renal fibrosis, which could be prevented by overexpression of miR-98-5p. Moreover, high mobility group A (HMGA2) can exhibit an important role in diverse biological processes. Here, HMGA2 was investigated as a target of miR-98-5p currently. Luciferase reporter assay was conducted and the correlation of miR-98-5p and HMGA2 was validated. Moreover, it was displayed that HMGA2 was remarkably elevated in db/db mice and mice mesangial cells. Furthermore, miR-98-5p strongly depressed HMGA2 protein and mRNA levels in mice mesangial cells. Overall, these revealed miR-98-5p could suppress the EMT process and renal fibrosis through targeting HMGA2 in DN.

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

“…As well known, EMT is a kind of biological course, and epithelial cells can transdifferentiate into mesenchymal cells in this process and is able to contribute to pathological fibrosis. 49 Interestingly, activation of both MAPKs and SMAD2/3 has been reported to be involved in the process of EMT. 50,51 In EMT process, transcription factor snail1 activated by high glucose would inhibit the transcription and production of epithelial marker ZO-1, epithelial cells activate, and then, transdifferentiate to mesenchymal cells, followed by the elevating expression of mesenchymal marker α-SMA.…”

“…As well known, EMT is a kind of biological course, and epithelial cells can transdifferentiate into mesenchymal cells in this process and is able to contribute to pathological fibrosis 49 . Interestingly, activation of both MAPKs and SMAD2/3 has been reported to be involved in the process of EMT 50,51 .…”

Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

“…Nevertheless, some miRNAs exert protective effects by inhibiting the epithelial-to-mesenchymal transition (EMT). Notably, miR-30c, miR-98-5p and miR-302a-3p target the fibrosis-related JAK1, Snail1, HMGA2, and ZEB1, respectively, thus blocking the fibrotic process in DKD by inhibiting EMT ( Zhao et al, 2017 ; Tang et al, 2018b ; Zhu et al, 2019c ; Gao et al, 2020 ). Furthermore, miR-455-3p also inhibits renal fibrosis by targeting ROCK2, together with the reduction of anti-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein 1 (MCP-1) ( Wu et al, 2018a ).…”

HMGA2-induced epithelial–mesenchymal transition is reversed by let-7d in intrauterine adhesions

“…High mobility group AT-hook 2 (HMGA2), a small non-histone protein of the HMGA family, is an important regulator in EMT of development and neoplasia process ( Fusco and Fedele, 2007 ; Fedele and Fusco, 2010 ; Macrì et al , 2016 ). More notably, HMGA2 has been implicated in EMT processes in some fibrotic diseases ( Wang et al , 2016a , b ; Hou et al , 2018 ; Zhu et al , 2019 ). Studies have reported that regulating HMGA2 expression prevented renal fibrogenesis and that loss of HMGA2 weakened EMT in tubular epithelial cells ( Wang et al , 2016a , b ; Zhu et al , 2019 ).…”

“…More notably, HMGA2 has been implicated in EMT processes in some fibrotic diseases ( Wang et al , 2016a , b ; Hou et al , 2018 ; Zhu et al , 2019 ). Studies have reported that regulating HMGA2 expression prevented renal fibrogenesis and that loss of HMGA2 weakened EMT in tubular epithelial cells ( Wang et al , 2016a , b ; Zhu et al , 2019 ). In addition, HMGA2 was also involved in EMT of pulmonary fibrosis and lens fibrosis through transforming growth factor (TGF)-β signaling pathways ( Wang et al , 2016a , b ; Hou et al , 2018 ).…”