miR‐124‐3p improves mitochondrial function of renal tubular epithelial cells in db/db mice

Abstract

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes mellitus (DM) and the main cause of end‐stage renal failure. However, the pathogenesis of DKD is complicated. In this study, we found that miR‐124‐3p plays a key role in regulating renal mitochondrial function and explored its possible mechanism in DKD progression by performing a series of in vitro and in vivo experiments. Decreased expression of miR‐124‐3p was found in db/db mice compared to db/m mice. Moreover, miR‐124‐3p down‐regulated FOXQ1 by targeting FOXQ1 mRNA 3′‐UTR in NRK‐52E cells. Also, an increase in FOXQ1 and down‐regulation of Sirt4 were found in db/db mouse kidney and renal tubular epithelial cells cultured with high glucose and high lipid. Overexpression of FOXQ1 could further down‐regulate the expression of Sirt4 and aggravate the damage of mitochondria. Conversely, the knockdown of the FOXQ1 gene induced Sirt4 expression and partially restored mitochondrial function. To verify the effects of miR‐124‐3p on Sirt4 and mitochondria, we found that miR‐124‐3p mimics could up‐regulate Sirt4 and inhibit ROS production and MitoSOX, thus restoring the number and morphology of mitochondria. These results showed that under high‐glucose and high‐lipid conditions, the down‐regulation of miR‐124‐3p induces FOXQ1 in renal tubular epithelial cells, which in turn suppresses Sirt4 and leads to mitochondrial dysfunction, promoting the development of DKD.

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“… 15 Under conditions of high glucose and high lipid, downregulation of miR-124-3p can induce FOXQ1 in renal tubular epithelial cells, thereby inhibiting SIRT4, leading to mitochondrial dysfunction, and promoting the occurrence of diabetic nephropathy. 33 In our experiments, we found that KLF6 silence could mitigate mitochondrial dysfunction in CSE-induced BEAS-2B cells through SIRT4 upregulation.…”

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“…FoxQ1 (up-regulated in H vs C, while down-regulated in HM vs H) is a member of forkhead box transcription factor family [ 29 ]. Liang et al found that expression of FoxQ1 was elevated in renal tubular epithelial cells under high-glucose, high-lipid conditions, and FoxQ1 inhibited Sirt4 expression, leading to mitochondrial dysfunction and promoting the development of DKD [ 30 ]. In addition, FoxQ1 is recognized as a driver of epithelial-mesenchymal transition (EMT) and metastasis in multiple cancer types [ 31 , 32 ].…”

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“…Yi et al have illuminated that the upregulation of SIRT4 in keratinocytes alleviates the senescence phenotype 28 . Furthermore, Liang et al have substantiated that the downregulation of SIRT4 exacerbates mitochondrial damage in renal tubular epithelial cells 29 . Additionally, Dai et al have unveiled the suppressive effect of SIRT4 on the inflammatory response in OA 30 .…”