Progression of chronic renal failure in focal segmental glomerulosclerosis: consequence of podocyte damage or of tubulointerstitial fibrosis?

Kriz, Wilhelm

doi:10.1007/s00467-003-1172-7

Cited by 28 publications

(10 citation statements)

References 45 publications

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“…It has been argued that the survival of a nephron after damage depends on the ongoing health of the glomerulus, rather than the tubule itself. 40,41 This observation is consistent with the proposed notion of Bowman's capsule progenitor cells. 31,32 What is clear is that, whether replacement of cells within existing nephrons or loss of those nephrons followed by interstitial fibrosis, no new nephrons arise.…”

supporting

confidence: 90%

Is There Such a Thing as a Renal Stem Cell?

Little¹,

Bertram

2009

Journal of the American Society of Nephrology

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supporting

confidence: 90%

Is There Such a Thing as a Renal Stem Cell?

Little¹,

Bertram

2009

Journal of the American Society of Nephrology

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“…The well-known predictive value of nonselective proteinuria for the subsequent progression of chronic kidney diseases 40 -44 is in favor of this notion. Although the notion of toxic effect of leaked serum proteins on podocytes is not new, 45 Kriz presented an elegant overview of the potential toxic role of serum proteins in the context of various experimental observations made over the past 30 yr. 46 We observed infrequent detached PLAP (ϩ) podocyte debris in Bowman's capsule 4 d after LMB2 injection ( Figure S6). This finding and the loss of podocalyxin, the most durable podocyte marker in our hands, observed 9 d after LMB2 injection ( Figure S4), suggest that at least some of the podocytes injured secondarily at the early phase were eventually lost from the glomerulus.…”

Section: Discussionmentioning

confidence: 99%

Podocyte Injury Damages Other Podocytes

Matsusaka

Sandgren

Shintani

et al. 2011

Journal of the American Society of Nephrology

108

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Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis. Loss of podocytes leads to glomerular sclerosis, the morphologic hallmark of chronic kidney disease. 1-5 A number of factors, including genetic, mechanical, and immunological stresses, as well as toxins, can cause podocyte injury. 6 -9 As podocyte deterioration is often relentless, the question as to whether the ongoing injury is a result of a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes per se has remained unresolved.Previously, we established a transgenic mouse line (NEP25), which expresses human (h) CD25 selectively on podocytes. 10 By injecting the hCD25-targeted recombinant immunotoxin, anti-Tac(Fv)-PE38 (LMB2), 11 podocyte-selective injury can be induced in NEP25 mice in a dose-dependent manner. With high-dose LMB2 (Ն1.25 ng/g BW), NEP25 mice develop massive nonselective proteinuria, severe glomerulosclerosis, and renal failure, and die within 14 d. With low-dose LMB2 (0.625 ng/g BW), NEP25 mice develop moderate proteinuria, which peaks 1 to 2 wk after injection and gradually decreases. Although LMB2 is rapidly cleared from the circulation with half life of 35 min, 11 podocyte injury progresses over weeks. Thus, 3 wk after injection, mice develop focal segmental glomerulosclerosis. With either dose, the injury is initially confined to podocytes, but later other cells

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“…Podocytes are unique glomerular epithelial cells which comprise the outermost layer of the glomerular filtration barrier [9–11]. Podocyte foot processes interdigitate with the counterparts of neighboring cells to form the slit diaphragm, which constitutes the final barrier to prevent protein loss from vascular to urinary space.…”

Section: Introductionmentioning

confidence: 99%

Epithelial-to-mesenchymal transition in podocytes mediated by activation of NADPH oxidase in hyperhomocysteinemia

Zhang

Xia

Boini

et al. 2011

Pflugers Arch - Eur J Physiol

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The present study tested the hypothesis that hyperhomocysteinemia (hHcys) induces podocytes to undergo epithelial-to-mesenchymal transition (EMT) through the activation of NADPH oxidase (Nox). It was found that increased homocysteine (Hcys) level suppressed the expression of slit diaphragm-associated proteins, P-cadherin and zonula occludens-1 (ZO-1) in conditionally immortalized mouse podocytes, indicating the loss of their epithelial features. Meanwhile, Hcys remarkably increased the abundance of mesenchymal markers, such as fibroblast specific protein-1 (FSP-1) and α-smooth muscle actin (α-SMA). These phenotype changes in podocytes induced by Hcys were accompanied by enhanced superoxide (O2.−) production, which was substantially suppressed by inhibition of Nox activity. Functionally, Hcys significantly enhanced the permeability of the podocyte monolayer coupled with increased EMT, and this EMT-related increase in cell permeability could be restored by Nox inhibitors. In mice lacking gp91phox (gp91−/−), an essential Nox subunit gene, hHcys-enhanced podocyte EMT and consequent glomerular injury were examined. In wild-type (gp91+/+) mice, hHcys induced by a folate-free (FF) diet markedly enhanced expression of mesenchymal markers (FSP-1 and α-SMA) but decreased expression of epithelial markers of podocytes in glomeruli, which were not observed in gp91−/− mouse glomeruli. Podocyte injury, glomerular sclerotic pathology, and marked albuminuria observed in gp91+/+ mice with hHcys were all significantly attenuated in gp91−/− mice. These results suggest that hHcys induces EMT of podocytes through activation of Nox, which represents a novel mechanism of hHcys-associated podocyte injury.

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Progression of chronic renal failure in focal segmental glomerulosclerosis: consequence of podocyte damage or of tubulointerstitial fibrosis?

Cited by 28 publications

References 45 publications

Is There Such a Thing as a Renal Stem Cell?

Is There Such a Thing as a Renal Stem Cell?

Podocyte Injury Damages Other Podocytes

Epithelial-to-mesenchymal transition in podocytes mediated by activation of NADPH oxidase in hyperhomocysteinemia

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