Glomerular diseases: genetic causes and future therapeutics

Chiang, Chih‐Kang; Inagi, Reiko

doi:10.1038/nrneph.2010.103

Cited by 52 publications

(59 citation statements)

References 167 publications

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“…45 Mutations of actin-binding proteins, such as a-actinin-4 or CD2AP, lead to podocyte injury because of disorganization of the actin cytoskeleton and disruption of its filtration barrier. 41,46,47 We performed a scratch assay and showed that SIRT1 was necessary for podocyte motility. Although the question of whether motile podocytes induce proteinuria and renal damage is still controversial, 8,41 it is widely accepted that the reorganization of actin cytoskeleton is necessary for podocyte migration.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

Motonishi¹,

Nangaku²,

Wada³

et al. 2015

Journal of the American Society of Nephrology

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Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation. However, the pathophysiologic role of SIRT1 in podocytes remains unclear. Here, we investigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1 pod2/2 ) mice. We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion and BUN and the severity of glomerular injury were all significantly greater in SIRT1 pod2/2 mice than in wild-type mice. Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1 pod2/2 mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1 pod2/2 mice compared with wild-type mice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H 2 O 2 -treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H 2 O 2 -induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and -polymerizing protein cortactin in the nucleus and facilitated deacetylated cortactin localization in the cytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin from F-actin, suggesting the necessity of cytoplasmic cortactin for maintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity.

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Section: Discussionmentioning

confidence: 99%

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

Motonishi¹,

Nangaku²,

Wada³

et al. 2015

Journal of the American Society of Nephrology

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“…The integrity of this barrier to maintain ultrafiltration of plasma depends on the proper expression and signaling of the components of the slit diaphragm (16)(17)(18). Several mutations in the gene that encodes nephrin (NPHS1), and other components of the slit diaphragm complex, have been described in patients with congenital nephrotic syndrome (14,19).…”

Section: Magi-2/s-scam | Glomerulosclerosismentioning

confidence: 99%

MAGI-2 scaffold protein is critical for kidney barrier function

Balbas¹,

Burgess

Murali

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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MAGUK Inverted 2 (MAGI-2) is a PTEN-interacting scaffold protein implicated in cancer on the basis of rare, recurrent genomic translocations and deletions in various tumors. In the renal glomerulus, MAGI-2 is exclusively expressed in podocytes, specialized cells forming part of the glomerular filter, where it interacts with the slit diaphragm protein nephrin. To further explore MAGI-2 function, we generated Magi-2-KO mice through homologous recombination by targeting an exon common to all three alternative splice variants. Magi-2 null mice presented with progressive proteinuria as early as 2 wk postnatally, which coincided with loss of nephrin expression in the glomeruli. Magi-2-null kidneys revealed diffuse podocyte foot process effacement and focal podocyte hypertrophy by 3 wk of age, as well as progressive podocyte loss. By 5.5 wk, coinciding with a near-complete loss of podocytes, Magi-2-null mice developed diffuse glomerular extracapillary epithelial cell proliferations, and died of renal failure by 3 mo of age. As confirmed by immunohistochemical analysis, the proliferative cell populations in glomerular lesions were exclusively composed of activated parietal epithelial cells (PECs). Our results reveal that MAGI-2 is required for the integrity of the kidney filter and podocyte survival. Moreover, we demonstrate that PECs can be activated to form glomerular lesions resembling a noninflammatory glomerulopathy with extensive extracapillary proliferation, sometimes resembling crescents, following rapid and severe podocyte loss.

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“…136,161 Proposed etiologic agents in ANCA disease include environmental toxins such as silica and infectious agents, including Gram-positive (S. aureus) and Gram-negative (Fim H adhesins) bacteria, viral infections, and several drugs. 122,[124][125][126][127][128] There also have been significant but low-level associations with potential susceptibility genes and their polymorphisms, including ANCA antigens, HLA, immune response proteins, Fc receptors, cytokines and others, but no high-level associations have been described, 163 other than DRB1*15 in African Americans. 164 The relatively frequent observation of ANCA antibodies in other autoimmune glomerular diseases including anti-GBM disease, lupus, and membranous nephropathy suggests that common etiologic or susceptibility factors may be present (Table 1).…”

Section: T Cellsmentioning

confidence: 99%

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Couser

2012

Journal of the American Society of Nephrology

179

155

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Genetically modified immune responses to infections and self-antigens initiate most forms of GN by generating pathogen-and danger-associated molecular patterns that stimulate Toll-like receptors and complement. These innate immune responses activate circulating monocytes and resident glomerular cells to release inflammatory mediators and initiate adaptive, antigen-specific immune responses that collectively damage glomerular structures. CD4 T cells are needed for B cell-driven antibody production that leads to immune complex formation in glomeruli, complement activation, and injury induced by both circulating inflammatory and resident glomerular effector cells. Th17 cells can also induce glomerular injury directly. In this review, information derived from studies in vitro, well characterized experimental models, and humans summarize and update likely pathogenic mechanisms involved in human diseases presenting as nephritis (postinfectious GN, IgA nephropathy, antiglomerular basement membrane and antineutrophil cytoplasmic antibodymediated crescentic GN, lupus nephritis, type I membranoproliferative GN), and nephrotic syndrome (minimal change/FSGS, membranous nephropathy, and C3 glomerulopathies). Advances in understanding the immunopathogenesis of each of these entities offer many opportunities for future therapeutic interventions.

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Glomerular diseases: genetic causes and future therapeutics

Cited by 52 publications

References 167 publications

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes

MAGI-2 scaffold protein is critical for kidney barrier function

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

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