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      Cell Cycle and Glomerular Disease: A Minireview

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          Globally, glomerular diseases are a leading cause of chronic and end-stage renal disease. In the mature glomerulus, under normal conditions, glomerular cells have a low turnover rate. However, in disease, a variety of pathophysiological stimuli can lead to disturbances in glomerular cell biology, including toxins, immune-mediated stresses, metabolic derangements, drugs, infections, hemodynamic changes, growth factors, and cytokines. Not only does the form of injury govern the histologic and clinical manifestations of disease, but also the nature of the response to injury. This response to injury is largely cell-type specific, and the glomerulus represents a rare microcosm of the larger organism in which one can study the cellular responses of three very distinct cell types: mesangial cells, visceral epithelial cells or podocytes, and endothelial cells. These cells can undergo several cell fates in response to injury, including proliferation, de-differentiation, hypertrophy, senescence, apoptosis, or necrosis. The regulation of these responses occurs at the level of the cell cycle, coordinated by positive regulators, cyclins and cyclin-dependent kinases, and negative regulators, cyclin-dependent kinase inhibitors. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the glomerular cellular response to injury. The recent advances in cell cycle biology in diseases of the mesangial cell and the podocyte are the focus of this minireview.

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          Most cited references 20

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          Cellular events in the evolution of experimental diabetic nephropathy.

          In several models of progressive glomerular disease, mesangial cell proliferation, phenotypic change and increased growth factor expression precede up-regulation of genes for extracellular matrix components (ECM) and mesangial expansion. To examine these events in diabetic nephropathy (DN) we conducted sequential studies of glomeruli in rats with streptozotocin induced DN. We found prominent mesangial cell proliferation at three days (4.34 +/- 2.24 PCNA + cells/glom vs. 1.6 +/- 0.74 in controls, P < 0.001) associated with increased alpha-actin expression. PDGF B-chain mRNA was slightly increased at day one, and PDGF B-chain immunostaining was slightly increased at days one and six. Staining for bFGF was significantly increased at three days (2.2 +/- 0.6 vs. 1.2 +/- 0.1 in controls, P < 0.01). There was also an early increase in platelets in glomeruli of diabetic animals, and platelet depletion significantly inhibited the early phase of proliferation. In addition to mesangial cell proliferation, a prominent glomerular macrophage infiltration began at day three and peaked at day 30 (3.94 +/- 1.47 vs. 2.08 +/- 1.13 in controls, P < 0.01). TGF-beta mRNA increased at days 14 and 30. Insulin treatment prevented mesangial cell proliferation, actin expression, and macrophage infiltration, and normalized TGF-beta expression at 14 and 30 days. These multiple cellular events preceded any detectable increases in glomerular gene expression or deposition of collagen I, IV or laminin.
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            Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies.

            Mature podocytes are growth-arrested because of the expression of cyclin-dependent kinase inhibitors. Under pathological conditions, podocytes may undergo mitosis, but not cell division. Exceptions to this rule are collapsing glomerulopathies (CGs), including HIV-associated nephropathy (HIVAN) and idiopathic CG, where podocytes undergo a dysregulation of their differentiated phenotype and proliferate. To shed light on the mechanism underlying podocyte proliferation in CG, we analyzed the expression of the proliferation marker Ki-67, cyclins (A, D1), cyclin-dependent kinase inhibitors (p27, p57), and podocyte differentiation marker synaptopodin in eight cases of HIVAN and two cases of idiopathic CG. Normal fetal and adult kidneys served as controls. Both HIVAN and idiopathic CG showed a marked reduction in the expression of p27, p57, and cyclin D1 (absent in 69, 62, and 80% of all glomeruli, respectively). Cyclin A and Ki-67 were expressed in 11 and 29% of all glomeruli. Moreover, there was partial loss of synaptopodin and cyclin D1 expression in nonaffected glomeruli. The loss of p27 and p57 leading to expression of cyclin A may account for the activation of podocyte proliferation in CG. Furthermore, the loss of cyclin D1 from histologically normal glomeruli suggests a possible role of cyclin D1 in mediating the dysregulation of the podocyte cell cycle in CG. These novel findings offer insight into the molecular regulation of mature podocyte differentiation. Podocyte proliferation in CG provides evidence in support of a previously underestimated plasticity of mature podocytes.
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              Podocyte expression of the CDK-inhibitor p57 during development and disease.

              The mature podocyte is a terminally differentiated cell with a limited proliferative capacity. The precise cell cycle proteins necessary for establishing podocyte quiescence during development or permitting podocyte cell cycle re-entry in disease states have not been fully defined. Accordingly, we studied the role of the cyclin dependent kinase (CDK)-inhibitor p57Kip2 (p57) in modulating these processes. The expression of p57 protein in relation to markers of DNA synthesis was examined in developing mouse kidneys, and in the passive Heymann nephritis (PHN) and anti-glomerular antibody models of glomerular disease by immunohistochemistry. The role of p57 in glomerulogenesis was explored by examining renal tissue from embryonic p57-/- mice, and the expression of p21, p27 and p57 protein and mRNA was examined in podocytes in vitro. The de novo expression of p57 during glomerulogenesis coincides with the cessation of podocyte proliferation, and the establishment of a mature phenotype, and p57 is expressed exclusively in podocytes in mature glomeruli. However, p57 knockout mice have normal glomerular podocyte development. In addition, mRNA but not protein levels of p57 increased upon differentiation of podocytes in vitro. There was a marked decrease in p57 expression in both animal models of podocyte injury. This was diffuse in PHN, whereas in the murine model, loss of expression of p57 occurred predominantly in proliferating podocytes, expressing proliferating cell nuclear antigen (PCNA). Despite the de novo expression of p57 protein coinciding with the cessation of primitive podocyte proliferation during glomerulogenesis, embryonic p57-/- mice glomeruli were histologically normal. Cultured podocytes did not require changes in p57 protein levels to undergo differentiation. These data suggest that p57 alone is not required for podocyte differentiation, and that other cell cycle regulators may play a role. Furthermore, although injury to mature podocytes in experimental glomerular disease is associated with a decrease in p57, the levels of all three members of the Cip/Kip family of CDK inhibitors appear to determine the capability of podocytes to proliferate.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                January 2006
                22 September 2005
                : 102
                : 2
                : e39-e48
                Division of Nephrology, Department of Medicine, University of Washington, Seattle, Wash., USA
                88400 Nephron Exp Nephrol 2006;102:e39–e48
                © 2006 S. Karger AG, Basel

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                Figures: 4, Tables: 1, References: 30, Pages: 1
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