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      Cell Cycle Regulatory Proteins in Podocyte Health and Disease

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          The glomerular visceral epithelial cell, or podocyte, is a highly specialized and terminally differentiated cell that is fundamental to the integrity of the glomerular filtration barrier and functions to prevent urinary protein leakage and to oppose intracapillary hydrostatic pressure. Common to many human kidney diseases and experimental animal models is a strong association between podocyte injury and the development of progressive kidney disease. Studies have shown that a decline in podocyte number strongly correlates with, and likely underlies, proteinuria and the progression to glomerulosclerosis. Maintenance of podocyte differentiation, essential to its normal structure and function, is challenged in the setting of glomerular injury, with very divergent outcomes dependent upon the inciting injury. In response to injury, podocytes may undergo several cell fates, including proliferation, de-differentiation, hypertrophy, apoptosis, or necrosis. Common to these potential outcomes of renal injury is their ultimate regulation at the level of the cell cycle. Positive regulators (cyclins and cyclin-dependent kinases) and negative regulators (cyclin-dependent kinase inhibitors) coordinate the cell cycle. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the cellular response to injury. Emerging lessons from mouse knockout experiments highlight that the cell cycle machinery operates differently in distinct cell types. Recent studies focusing on the roles of cell cycle regulatory proteins specifically in podocytes have provided important clues on how these proteins operate to constrain cell proliferation and preserve differentiation in health, and how they modulate the dysregulated phenotype in diseased states. In disease, both a failure to regenerate lost podocytes and an inappropriate proliferative response can have profound consequences for glomerular structure and function. Here, we will review the latest advances in understanding the roles of cell cycle regulatory proteins in diseases of the podocyte.

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          Most cited references 17

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          Direct effects of dexamethasone on human podocytes.

          Glucocorticoids are widely used in the treatment of human glomerular diseases, but their mode of action is poorly understood particularly in steroid-sensitive nephrotic syndrome, which is most common in childhood and is characterized by a lack of inflammation in the kidney. The podocyte is a key cell in the glomerulus in health and disease: until recently, human podocytes have been difficult to study in vitro. We have developed a conditionally immortalized human podocyte cell line transfected with a temperature-sensitive simian virus 40 transgene: when the transgene is inactivated in vitro, these cells adopt the phenotype of differentiated podocytes. We have used these cells to evaluate, using immunocytochemistry, reverse transcriptase-polymerase chain reaction, and Western blotting, direct effects of the glucocorticoid dexamethasone at concentrations designed to mimic in vivo therapeutic corticosteroid levels. Dexamethasone upregulated expression of nephrin and tubulin-alpha, and downregulated vascular endothelial growth factor. Effects on cell cycle were complex with downregulation of cyclin kinase inhibitor p21 and augmentation of podocyte survival, without any effect on apoptosis. We report cytokine production by human podocytes, especially interleukin (IL)-6 and -8; IL-6 expression was suppressed by dexamethasone. These potent direct effects on podocytes illustrate a novel mode of action of glucocorticoids and suggest potential new therapeutic strategies for glomerular disease.
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            Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2-related family proteins.

            Nephrotic-range proteinuria is due to glomerular diseases characterized by podocyte injury. Glucocorticoids are the standard of care for most forms of nephrotic syndrome. However, the precise mechanisms underlying the beneficial effects of glucocorticoids on podocytes, beyond its general immunosuppressive and anti-inflammatory effects, are still unknown. This study tested the hypothesis that the synthetic glucocorticoid dexamethasone directly reduces podocyte apoptosis. Growth-restricted immortalized mouse podocytes in culture were exposed to puromycin aminonucleoside (PA) to induce apoptosis. Our results showed that dexamethasone significantly reduced PA-induced apoptosis by 2.81-fold. Dexamethasone also rescued podocyte viability when exposed to PA. PA-induced apoptosis was associated with increased p53 expression, which was completely blocked by dexamethasone. Furthermore, the inhibition of p53 by the p53 inhibitor pifithrin-alpha protected against PA-induced apoptosis. Dexamethasone also lowered the increase in the proapoptotic Bax, which was increased by PA, and increased expression of the antiapoptotic Bcl-xL protein. Moreover, the decrease in p53 by dexamethasone was associated with increased Bcl-xL levels. Podocyte apoptosis induced by PA was caspase-3 independent but was associated with the translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. AIF translocation was inhibited by dexamethasone. These results show that PA-induced podocyte apoptosis is p53 dependent and associated with changes in Bcl-2-related proteins and AIF translocation. The protective effects of dexamethasone on PA-induced apoptosis were associated with decreasing p53, increasing Bcl-xL, and inhibition of AIF translocation. These novel findings provide new insights into the beneficial effects of corticosteroids on podocytes directly, independent of its immunosuppressive effects.
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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.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 2007
                06 June 2007
                : 106
                : 2
                : e51-e59
                Division of Nephrology, University of Washington, Seattle, Wash., USA
                101793 Nephron Exp Nephrol 2007;106:e51–e59
                © 2007 S. Karger AG, Basel

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                Figures: 1, References: 20, Pages: 1


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