Mechanical stretch induces angiotensinogen expression through PARP1 activation in kidney proximal tubular cells.

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) contributes to fibrosis in several disease models. Recent in vivo data indicate that loss of PARP1 attenuates renal fibrosis and inflammation independent on transforming growth factor-β (TGF-β); however, the role of PARP1 in kidney tubular cells in response to tubulointerstitial fibrosis remains to be defined. Here, we report that PARP1 activation after mechanical stretch of kidney proximal tubular cells enhances angiotensinogen expression via nuclear factor kappa B (NF-κB) activation. Mechanical stretch for 24 h increased PARP1 expression and activation in mouse cortical proximal tubular (MCT) cells. Treatment with 3-aminobenzamide, a PARP1 inhibitor, efficaciously reduced the PARP1 activation induced by mechanical stretch. PARP1 inhibition also reduced angiotensinogen expression and NF-κB p65 phosphorylation induced by mechanical stretch. TGF-β1 expression and secretion were enhanced by mechanical stretch, but PARP1 inhibition did not change the levels of TGF-β1. These data demonstrate that mechanical stretch-induced PARP1 activation contributes to angiotensinogen expression and NF-κB activation in kidney proximal tubular cells, resulting in the promotion of renal tubulointerstitial fibrosis and inflammation.