Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice.

ABSTRACT: Glycogen synthase kinase-3? (GSK3?) is a serine/threonine protein kinase that plays an important role in renal tubular injury and regeneration in acute kidney injury. However, its role in the development of renal fibrosis, often a long-term consequence of acute kidney injury, is unknown. Using a mouse model of renal fibrosis induced by ischemia-reperfusion injury, we demonstrate increased GSK3? expression and activity in fibrotic kidneys, and its presence in myofibroblasts in addition to tubular epithelial cells. Pharmacological inhibition of GSK3 using TDZD-8 starting before or after ischemia-reperfusion significantly suppressed renal fibrosis by reducing the myofibroblast population, collagen-1 and fibronectin deposition, inflammatory cytokines, and macrophage infiltration. GSK3 inhibition in vivo reduced TGF-?1, SMAD3 activation and plasminogen activator inhibitor-1 levels. Consistently in vitro, TGF-?1 treatment increased GSK3? expression and GSK3 inhibition abolished TGF-?1-induced SMAD3 activation and ?-smooth muscle actin (?-SMA) expression in cultured renal fibroblasts. Importantly, overexpression of constitutively active GSK3? stimulated ?-SMA expression even in the absence of TGF-?1 treatment. These results suggest that TGF-? regulates GSK3?, which in turn is important for TGF-?-SMAD3 signaling and fibroblast-to-myofibroblast differentiation. Overall, these studies demonstrate that GSK3 could promote renal fibrosis by activation of TGF-? signaling and the use of GSK3 inhibitors might represent a novel therapeutic approach for progressive renal fibrosis that develops as a consequence of acute kidney injury.

SUBMITTER: Singh SP 

PROVIDER: S-EPMC4527294 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature