Abstract
The role of p53 in renal fibrosis has recently been suggested, however, its function remains controversial and the underlying mechanism is unclear. Here, we show that pharmacological and genetic blockade of p53 attenuated renal interstitial fibrosis, apoptosis, and inflammation in mice with unilateral urethral obstruction (UUO). Interestingly, p53 blockade was associated with the suppression of miR-215-5p, miR-199a-5p&3p, and STAT3. In cultured human kidney tubular epithelial cells (HK-2), TGF-β1 treatment induced fibrotic changes, including collagen I and vimentin expression, being associated with p53 accumulation, p53 Ser15 phosphorylation, and miR-199a-3p expression. Inhibition of p53 by pifithrin-α blocked STAT3 activation and the expression of miR-199a-3p, collagen I, and vimentin during TGF-β1 treatment. Over-expression of miR-199a-3p increased TGFβ1-induced collagen I and vimentin expression and restored SOCS7 expression. Furthermore, SOCS7 was identified as a target gene of miR-199a-3p, and silencing of SOCS7 promoted STAT3 activation. ChIp analyses indicated the binding of p53 to the promoter region of miR-199a-3p. Consistently, kidney biopsies from patients with IgA nephropathy and diabetic nephropathy exhibited substantial activation of p53 and STAT3, decreased expression of SOCS7, and increase in profibrotic proteins and miR-199a-3p. Together, these results demonstrate the novel p53/miR-199a-3p/SOCS7/STAT3 pathway in renal interstitial fibrosis.
Highlights
Renal interstitial fibrosis, characterized by excessive accumulation of extracellular matrix (ECM), leads to progressive decline in renal function and is a common pathological process of chronic kidney disease (CKD)[1,2]
We found that the expression of fibronectin, collagen I, and α-SMA was markedly increased in wild-type mice with urethral obstruction (UUO) than in the Sham group on day 7, which was significantly reduced in p53-KO mice (Fig. 5A,B). p53 expression in UUO was notably lower in p53 KO kidney tissues than that in wild-type tissues, verifying p53 ablation in knockout mice
We found that TGF-β1 treatment markedly increased activation of STAT3 and the expression of collagen I, vimentin, and miR-199a-3p, and reduced SOCS7 protein, which was significantly reversed by pifithrin-αtreatment (Fig. 8F–H)
Summary
The pathologic role of p53 in renal fibrosis has been suggested. p53 inhibitors suppressed renal fibrosis in post-ischemic kidneys[11]. By using ChIp assays, we demonstrated that p53 could physically interact with the promoter region of miR-199a-3p, which is supported by the work of Wang et al.[43] These data suggest a novel regulatory mechanism by which p53 upregulates STAT3 activation by direct inducing miR199a-3p to suppress SOCS7 in HK-2 cells (Fig. 11). This mechanism seems to be true in HK-2 cells, and in mice and fibrotic kidney samples from IgAN and DN patients. In HK-2 cells and mouse models, inhibition of p53 suppressed STAT3 activation, a key signaling of renal fibrosis, by inducing miR199a-3p that represses SOCS7. Our present study suggests that p53 may be a therapeutic target of renal fibrosis in chronic kidney diseases
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