Cross Talk In The Regulation Of Mir-192 By P53: An Amplification Loop In The Pathogenesis Of Diabetic Nephropathy
FASEB JOURNAL(2012)
摘要
TGF‐β activates microRNA (miR) amplification circuits that include miR‐192 in mouse mesangial cells (MMCs) which regulate downstream events leading to diabetic nephropathy (DN). miR‐192 can downregulate Zeb2 and increase collagen expression and fibrosis. p53 regulates miR‐192 expression in cancer cells. Here we examined whether a cross talk between miR‐192 and p53 in MMCs can result in their mutually increased expression and amplification of downstream pathways related to DN. Primary WT, p53‐knockout (KO) and miR‐192‐KO MMCs were used to analyze effects of p53 and miR‐192 on each other. Kidney samples from diabetic, and locked‐nucleic‐acid (LNA) modified anti‐miR‐192 oligonucleotides treated diabetic mice were analyzed for p53 levels. p53‐KO MMCs showed lower expression of miR‐192, collagen and p21 but higher levels of Zeb2. Exogenous p53 increased miR‐192 promoter activity in p53KO MMCs. TGF‐β induced miR‐192 expression was diminished in p53‐KO MMCs. miR‐192‐KO MMCs had decreased p53 protein expression. miR‐192 mimics or Zeb2 siRNA increased p53 promoter activity and miR‐192 mimics increased p53 protein levels in WT MMCs. Increased p53 staining was observed in kidney glomeruli of diabetic mice relative to controls and this was attenuated by LNA‐anti‐ miR‐192. These results suggest that the reciprocal regulation of miR‐192 and p53 can amplify pathogenic signals in chronic kidney diseases such as DN. Source of research support ‐ NIH DK081705 and NIH DK058191
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p53
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