p53 induces miR199a-3p to suppress SOCS7 for STAT3 activation and renal fibrosis in UUO

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.

p53 induces miR‐199a‐3p to suppress mechanistic target of rapamycin activation in cisplatin‐induced acute kidney injury

“…Several miRNAs appear to be pathogenic by promoting inflammation, apoptosis, and fibrosis while other miRNAs may be protective in AKI . Zhang reported that p53 induced miR‐199a‐3p to suppress SOCS7 for STAT3 activation and renal fibrosis in unilateral urethral obstruction . However, miR‐199a‐3p can also regulate p53 expression by targeting CABLES1 in mouse cardiac c‐Kit + cells to promote proliferation and inhibit apoptosis through a negative feedback loop .…”

Intestinal fibrosis

“…Yang and colleagues recently provided a mechanism by which p53 blockade attenuated experimental kidney fibrosis. It appears to signal through the microRNA miR-199a-3p, SOCS7 and STAT3 and the changes in this pathway could be recapitulated in human kidney fibrosis (55•). …”

Chikungunya virus modulates the miRNA expression patterns in human synovial fibroblasts

“…The SOCS 1, SOCS2, and SOCS3 have been well characterized, especially SOCS2 suppression leads to osteoarthritis . Further, the suppression of SOCS7 has been reported to activate STAT3 protein which promotes inflammation . The STAT3 has been reported to either activate the immune responses through IL‐6 or suppress the inflammatory responses by activating the antiinflammatory cytokine IL‐10 signaling .…”