USP25 inhibits renal fibrosis by regulating TGF beta-SMAD signaling pathway in Ang II-induced hypertensive mice

Renal fibrosis is a crucial pathological feature of hypertensive renal disease (HRD). In-depth analysis of the pathogenesis of fibrosis is of great significance for the development of new drugs for the treatment of HRD. USP25 is a deubiquitinase that can regulate the progression of many diseases, but its function in the kidney remains unclear. We found that USP25 was significantly increased in human and mice HRD kidney tissues. In the HRD model induced by Ang II, USP25(-/-) mice showed significant aggravation of renal dysfunction and fibrosis compared with the control mice. Consistently, AAV9-mediated overexpression of USP25 significantly improved renal dysfunction and fibrosis. Mechanistically, USP25 inhibited the TGF-beta pathway by reducing SMAD4 K63-linked polyubiquitination, thereby suppressing SMAD2 nuclear translocation. In conclusion, this study demonstrates for the first time that the deubiquitinase USP25 plays an important regulatory role in HRD.

Automated summary

Renal fibrosis is a crucial feature of hypertensive renal disease (HRD). The deubiquitinase USP25 plays an important regulatory role in HRD by inhibiting the TGF-beta pathway and suppressing SMAD2 nuclear translocation. This study provides new insights into the pathogenesis of HRD and suggests that USP25 may be a potential target for drug development.