MAD2B contributes to parietal epithelial cell activation and crescentic glomerulonephritis via Skp2.

MAD2B contributes to parietal epithelial cell activation and crescentic glomerulonephritis via Skp2. Am J Physiol Renal Physiol. 2020 Aug 24;: Authors: Ye C, Xiong W, Lei CT, Tang H, Su H, Yi F, Zhang C Abstract Mitotic spindle assembly checkpoint protein 2 (MAD2B), a well-known anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase ζ, is critical for mitotic control and DNA repair. Previously, we detected a strong increase of MAD2B in the glomeruli from crescentic glomerulonephritis patients and anti-glomerular basement membrane (anti-GBM) rats, which predominantly originated from activated parietal epithelial cells (PECs). Consistently, in vitro MAD2B was increased in tumor necrosis factor-α (TNF-α)-treated PECs, along with cell activation and proliferation, as well as extracellular matrix accumulation, which could be reversed by MAD2B genetic depletion. Furthermore, we found that the expression of Skp2, an APC/CCDH1 substrate, was increased in the glomeruli of anti-GBM rats and TNF-α-stimulated PECs and could be suppressed by MAD2B depletion. Additionally, genetic deletion of Skp2 inhibited TNF-α-induced PEC activation and dysfunction. Finally, TNF-α blockade or glucocorticoid therapy administered to anti-GBM rats could ameliorate MAD2B and Skp2 accumulation, as well as weaken PEC activation. Collectively, our data suggest that MAD2B has a pivotal role in the pathogenesis of glomerular P...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research