| First Author | Singh SP | Year | 2015 |
| Journal | Dis Model Mech | Volume | 8 |
| Issue | 8 | Pages | 931-40 |
| PubMed ID | 26092126 | Mgi Jnum | J:225511 |
| Mgi Id | MGI:5693454 | Doi | 10.1242/dmm.020511 |
| Citation | Singh SP, et al. (2015) Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice. Dis Model Mech 8(8):931-40 |
| abstractText | Glycogen synthase kinase-3beta (GSK3beta) 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 GSK3beta 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-beta1, SMAD3 activation and plasminogen activator inhibitor-1 levels. Consistently in vitro, TGF-beta1 treatment increased GSK3beta expression and GSK3 inhibition abolished TGF-beta1-induced SMAD3 activation and alpha-smooth muscle actin (alpha-SMA) expression in cultured renal fibroblasts. Importantly, overexpression of constitutively active GSK3beta stimulated alpha-SMA expression even in the absence of TGF-beta1 treatment. These results suggest that TGF-beta regulates GSK3beta, which in turn is important for TGF-beta-SMAD3 signaling and fibroblast-to-myofibroblast differentiation. Overall, these studies demonstrate that GSK3 could promote renal fibrosis by activation of TGF-beta 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. |
