Abstract
Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor (TGF)-β1-inducible focal adhesion protein. We previously demonstrated that Hic-5 was localized in mesangial cells and its expression was associated with glomerular cell proliferation and matrix expansion in human and rat glomerulonephritis (GN). In the present study, we first assessed the role of Hic-5 in mesangioproliferative GN by injecting Habu venom into heminephrectomized wild type (Hic-5+/+) and Hic-5-deficient (Hic-5-/-) mice. Hic-5+/+ GN mice exhibited glomerular cell proliferation on day 7. Surprisingly, glomerular cell number and Ki-67-positive cells in Hic-5-/- GN mice were significantly greater than those in Hic-5+/+ GN mice on day 7, although the number of glomerular apoptotic cells and the expression of growth factors (platelet-derived growth factor-BB and TGF-β1) and their receptors were similarly increased in both Hic-5+/+ and Hic-5-/- GN mice. In culture experiments, proliferation assays showed that platelet-derived growth factor-BB and TGF-β1 enhanced the proliferation of Hic-5-/- mesangial cells compared with Hic-5+/+ mesangial cells. In addition, mitogenic regulation by Hic-5 was associated with altered and coordinated expression of cell cycle-related proteins including cyclin D1 and p21. The present results suggest that Hic-5 might regulate mesangial cell proliferation in proliferative GN in mice. In conclusion, modulation of Hic-5 expression might have a potential to prevent mesangial cell proliferation in the acute mitogenic phase of glomerulonephritis.
Highlights
Progressive glomerular diseases are generally characterized by increased cell proliferation and extracellular matrix (ECM) accumulation, both of which lead to glomerulosclerosis [1]
We focused on the investigation of the role of Hydrogen peroxide-inducible clone-5 (Hic-5) on Mesangial cell (MC) proliferation, because the expression of hydrogen peroxide-inducible clone (Hic)-5 was mainly localized in MCs and enhanced during glomerular injury
These results suggested that Hic-5 did not affect the glomerular expression of platelet-derived growth factor (PDGF)-B chain, transforming growth factor (TGF)-β1, or their receptors before or after glomerular injury (Fig 6)
Summary
Progressive glomerular diseases are generally characterized by increased cell proliferation and extracellular matrix (ECM) accumulation, both of which lead to glomerulosclerosis [1]. Glomerulosclerosis, an irreversible pathological change, is a final common pathway of injured glomeruli in all progressive glomerular diseases including IgA nephropathy and diabetic nephropathy [2,3]. Mesangial cell (MC) proliferation, the representative initial hallmark of glomerular injury, generally precedes glomerulosclerosis and often persists during the progressive course of glomerular.
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