Gene expression profile in streptozotocin-induced diabetic mice kidneys undergoing glomerulosclerosis

Wada, Jun; Zhang, Hong; Tsuchiyama, Yoshinori; Hiragushi, Keita; Hida, Kazuyuki; Shikata, Kenichi; Kanwar, Yashpal S.; Makino, Hírofumi

doi:10.1046/j.1523-1755.2001.0590041363.x

Cited by 63 publications

(49 citation statements)

References 43 publications

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“…Herein, microarray technology has become a standard tool for generation of gene expression profiles in various types of tissue. 3 Gene expression profiles have been generated in experimental 4 or human renal diseases such as lupus nephritis 5 or focal segmental glomerulosclerosis, 6 in circulating leukocytes of patients with different renal diseases, 7 in streptozotocin-induced diabetic nephropathy, 8 and anti-glomerular basement membrane GN. 9 Izumi et al 10 investigated the gene expression profile on certain days of experimental mesangial proliferative GN.…”

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Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration

Daniel

Lüdke

Wagner

et al. 2012

Laboratory Investigation

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Mesangial cell (MC) migration is essential during glomerular repair and kidney development. The aim of the study was to identify marker/player for glomerular progenitor/reserve cells migrating into the glomerulus after MC injury and during glomerulogenesis in the rat. Experimental mesangial proliferative nephritis was induced in Sprague Dawley rats by intravenous injection of OX-7 antibody. We investigated mRNA expression profiles in isolated glomeruli from on days 0, 1, 2, 3, and 5 after induction of anti-Thy1 nephritis using Affymetrix microarray technology. Using self-organizing maps, transgelin was identified as a new marker for repopulating glomerular cells. Expression of transgelin during anti-Thy1 nephritis was investigated by northern blot, real-time PCR, western blot, and immunohistochemistry. Migration and proliferation assays using isolated MCs after transgelin knockdown by siRNA were performed to investigate the potential role of transgelin during glomerular repopulation. Transgelin mRNA was not detected in healthy glomeruli. It was strongly upregulated during the repopulation process starting on day 1, continued to be increased until day 5 and disappeared on day 7. Transgelin was specifically expressed at the edge of the migratory front during glomerular repopulation as indicated by transgelin/OX-7 double staining. Transgelin expression was similar in migrating vs non-migrating MCs in vitro. Blocking of transgelin expression by siRNA treatment resulted in inhibition of MC migration and proliferation. Transgelin was also expressed in MCs during glomerulogenesis and in biopsies from patients with IgA nephritis. In conclusion, transgelin in the kidney is upregulated in repopulating MCs in vivo and supports their migratory and proliferative repair response after injury.

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Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration

Daniel

Lüdke

Wagner

et al. 2012

Laboratory Investigation

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“…1,2 Similar to other epithelial cell types, TGF-␤ stimulation induces apoptosis, growth inhibition, or differentiation in podocytes. [3][4][5] TGF-␤1 transgenic mice (TGF-␤1tg) are characterized by podocyte apoptosis at the onset of proteinuria and progressive glomerulosclerosis associated with progressive podocyte depletion. 3 Podocyte depletion is considered a hallmark of glomerular diseases characterized by segmental or global glomerulosclerosis.…”

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TβRI Independently Activates Smad- and CD2AP-Dependent Pathways in Podocytes

Xavier¹,

Niranjan²,

Krick³

et al. 2009

Journal of the American Society of Nephrology

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TGF-␤ regulates differentiation, growth, and apoptosis of podocytes and mediates podocyte depletion in glomerulosclerosis. TGF-␤ promotes proapoptotic signaling mediated by Smad3 but also activates prosurvival pathways such as phosphoinositide-3 kinase (PI3K)/AKT; the latter requires the CD2-associated adaptor protein (CD2AP) in podocytes. Whether the opposing activities mediated by Smad proteins and CD2AP involve molecular cross-talk is unknown. Here, we report that CD2AP-dependent early activation of the antiapoptotic PI3K/AKT pathway does not require TGF-␤ receptor-regulated Smad2 and Smad3. We found that the C-terminal region of CD2AP interacts directly with the cytoplasmic tail of the TGF-␤ receptor type I (T␤RI) in a kinase-dependent manner and that the interaction between the T␤RI and the p85 subunit of PI3K requires CD2AP. Consistent with the proapoptotic function of Smad signaling, Smad2/3-deficient podocytes were hyperproliferative and resistant to TGF-␤-induced growth inhibition and apoptosis. In contrast, CD2AP-deficient cells were hypoproliferative and hypersensitive to TGF-␤-induced apoptosis. In vivo, to determine the effects of reduced Smad3 or CD2AP gene dosage on podocyte apoptosis and proteinuria characteristic of TGF-␤1 transgenic mice, we generated TGF-␤1 transgenic mice deficient for Smad3 or heterozygous for CD2AP. Smad3 deficiency ameliorated podocyte apoptosis, and CD2AP heterozygosity increased both podocyte apoptosis and proteinuria. These data define distinct canonical (Smad) and noncanonical (CD2AP/PI3K/AKT) pathways that arise from direct, independent interactions with the T␤RI and that mediate opposing signals for podocyte death or survival.

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“…While albuminuria can regress in up to 50% of patients (5), the extent of mesangial matrix expansion correlates closely with progression of nephropathy (6); therefore, genes that can predict the development of mesangial matrix expansion are highly relevant. Recent reports have identified genes by microarray screens whose expression in kidneys of diabetic animals is either increased or decreased compared with controls (7,8). However, it is often difficult to select individual genes from microarray datasets that are associated with (and can therefore diagnose) a single phenotypic outcome.…”

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Molecular Profiling of Diabetic Mouse Kidney Reveals Novel Genes Linked to Glomerular Disease

et al. 2004

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To describe gene expression changes that characterize the development of diabetic nephropathy, we performed microarray and phenotype analysis on kidneys from db/db mice (a model of type 2 diabetes), streptozotocininduced diabetic C57BL/6J mice (a model of type 1 diabetes), and nondiabetic controls. Statistical comparisons were implemented based on phenotypic outcome characteristics of the animals. We used weighted votebased supervised analytical methods to find genes whose expression can classify samples based on the presence or absence of mesangial matrix expansion, the best indicator for the development of end-stage renal disease in humans. We identified hydroxysteroid dehydrogenase-3␤ isotype 4 and osteopontin as lead classifier genes in relation to the mesangial matrix expansion phenotype. We used the expression levels of these genes in the kidney to classify a separate group of animals for the absence or presence of diabetic glomerulopathy with a high degree of precision. Immunohistochemical analysis of murine and human diabetic kidney samples showed that both markers were expressed in podocytes in the glomeruli and followed regulation similar to that observed in the microarray. The application of phenotype-based statistical modeling approaches has led to the identification of new markers for the development of diabetic kidney disease. Diabetes 53: 784 -794, 2004

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Gene expression profile in streptozotocin-induced diabetic mice kidneys undergoing glomerulosclerosis

Abstract: Hyperglycemia is a major determinant of glomerulosclerosis in STZ-induced diabetic CD-1 mice, and the altered gene expression in the early phase of diabetic kidney may be critical for the development of diabetic nephropathy.

Cited by 63 publications

References 43 publications

Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration

Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration

TβRI Independently Activates Smad- and CD2AP-Dependent Pathways in Podocytes

Molecular Profiling of Diabetic Mouse Kidney Reveals Novel Genes Linked to Glomerular Disease

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