Podocyte injury in focal segmental glomerulosclerosis: Lessons from animal models (a play in five acts)
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Glomerulosclerosis
Glomerulosclerosis
Nephrin
Glomerulus
Podocin
Renal glomerulus
Slit diaphragm
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Podocyte injury is a hallmark of glomerular diseases, however, the intrinsic mechanisms are not elucidated. Previous studies have shown that B7-1 may be an inducer to podocyte injury. However, the intrinsic role of B7-1 in podocyte injury is controversial. In this study, we have identified that podocyte B7-1 definitely contributes to cell injury and glomerulosclerosis, and the underlying mechanisms are intimately correlated with activation of β-catenin pathway. Our studies provide the importance evidence to the role of B7-1 in podocyte injury and development of glomerulosclerosis.
Glomerulosclerosis
Cell injury
Renal Injury
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Glomerular capillary hypertension is a final common pathway to glomerulosclerosis. Because podocyte loss is an early event in the development of glomerulosclerosis, it is logical that the deleterious effects of glomerular capillary hypertension involve podocyte injury. Yet, the mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein activated in various disease states of the podocyte and accelerates renal injury, as evidenced by the milder course of experimental diabetic nephropathy in SPARC-null mice compared with diabetic SPARC wild-type mice. Accordingly, we tested the hypothesis that mechanical strain activates SPARC in podocytes and thus is a putative mediator of podocyte injury in states of intraglomerular capillary hypertension. Conditionally immortalized mouse podocytes were subjected to 10% cyclical stretch while nonstretched cells served as controls. SPARC levels were measured in whole cell lysate and cell media. Immunostaining was performed for SPARC in an experimental model of glomerular capillary hypertension. Our results demonstrate cyclical stretch of podocytes markedly increased SPARC levels in cell lysate, through activation of p38, as well as secreted SPARC. Relevance was shown by demonstrating increased podocyte staining for SPARC in the uninephrectomized spontaneously hypertensive rat. In conclusion, we have made the novel observation that mechanical forces characteristic of states of glomerular capillary hypertension lead to increased levels of SPARC in podocytes. We speculate that the increase in SPARC may be maladaptive and lead to a progressive reduction in podocyte number, thus fueling the future development of glomerulosclerosis.
Glomerulosclerosis
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<b><i>Background:</i></b> Focal segmental glomerulosclerosis (FSGS) is a histologic pattern characterized by focal glomerular scarring, which often progresses to systemic and diffuse glomerulosclerosis. Previous studies have emphasized that the initiation of classic FSGS occurs in podocytes. The dysfunction and loss of podocytes have been associated with the development of proteinuria and the progression of various diseases. In addition, primary, secondary, and genetic FSGS are caused by different mechanisms of podocyte injury. <b><i>Summary:</i></b> The potential sources and mechanism of podocyte supplementation are the focus of our current research. Increasing attention has been paid to the role played by parietal epithelial cells (PECs) during the progression of FSGS. PECs are not only the primary influencing factors in glomerulosclerosis lesions but also have repair abilities, which remain a focus of debate. Notably, other resident glomerular cells also play significant roles in the progression of this disease. <b><i>Key Message:</i></b> In this review, we focus on the mechanism of scarring in FSGS and discuss current and potential therapeutic strategies.
Glomerulosclerosis
Minimal change disease
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Glomerular disease is characterized by proteinuria and glomerulosclerosis, two pathologic features caused by podocyte injury and mesangial cell activation, respectively. However, whether these two events are linked remains elusive. Here, we report that sonic hedgehog (Shh) is the mediator that connects podocyte damage to mesangial activation and glomerulosclerosis. Shh was induced in glomerular podocytes in various models of proteinuric chronic kidney diseases (CKD). However, mesangial cells in the glomeruli, but not podocytes, responded to hedgehog ligand. In vitro, Shh was induced in podocytes after injury and selectively promoted mesangial cell activation and proliferation. In a miniorgan culture of isolated glomeruli, Shh promoted mesangial activation but did not affect the integrity of podocytes. Podocyte-specific ablation of Shh in vivo exhibited no effect on proteinuria after adriamycin injection but hampered mesangial activation and glomerulosclerosis. Consistently, pharmacologic blockade of Shh signaling decoupled proteinuria from glomerulosclerosis. In humans, Shh was upregulated in glomerular podocytes in patients with CKD and its circulating level was associated with glomerulosclerosis but not proteinuria. These studies demonstrate that Shh mechanistically links podocyte injury to mesangial activation in the pathogenesis of glomerular diseases. Our findings also illustrate a crucial role for podocyte-mesangial communication in connecting proteinuria to glomerulosclerosis.
Glomerulosclerosis
Mesangial cell
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Podocyte dysfunction is linked to progressive glomerular filtration barrier failure and glomerulosclerosis. A detailed sequence of structural alterations is now used to define three general modes of podocyte damage, highlighting degenerative, inflammatory, or dysregulative pathways to
Glomerulosclerosis
Kidney Glomerulus
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Glomerular visceral epithelial cells, also known as podocytes, are highly specialized epithelial cells that cover the outer layer of the glomerular basement membrane (GBM). Podocytes serve as the final barrier to urinary protein loss through the special formation and maintenance of foot processes (FPs) and an interposed slit diaphragm (SD). Chronic podocyte injury may cause podocyte detachment from the GBM, which leads to glomerulosclerosis. The elucidation of podocyte biology during the last decade has significantly improved our understanding of the pathophysiologic processes of proteinuria and glomerulosclerosis. This review highlights some of the recent findings for translating podocyte biology into new therapies and examinations for podocyte injury.
Slit diaphragm
Glomerulosclerosis
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Glomerulosclerosis
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Glomerulosclerosis
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