Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β?

Carew, Rosemarie M.; Sadagurski, Marianna; Goldschmeding, Roel; Martin, Finian; White, Morris F.; Brazil, Derek P.

doi:10.1186/1471-213x-10-73

Cited by 18 publications

(27 citation statements)

References 45 publications

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“…2A). Interestingly, this global reduction of organ size without obvious effects on structural organization has also been reported in the brain and kidney: Irs2 -deficient mice are born with a 35% reduction of brain size [44] and kidney size is reduced by 20% at P5 [45]. Although the brain and kidney are noticeably smaller in Irs2 -deficient mice, all areas are present but reduced proportionally.…”

Section: Discussionsupporting

confidence: 52%

Insulin Receptor Substrate 2 Is Required for Testicular Development

2013

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Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. Clinical studies suggest that diabetes and obesity diminish male fertility. However, the role of IRS proteins in male reproduction is unknown. We observed that testis weight is reduced by 45% in Irs2-deficient mice as compared with control males. The weight of these organs in Irs1 −/− males was similar to controls; however, since Irs1-deficient mice are 50% smaller, testis weight:body weight was increased in this model. Neonatal Irs2 −/− mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development. Histological examination of testicular cross sections from Irs2 −/− mice revealed normal cellular associations without obvious abnormalities in the seminiferous epithelium. Reduced testicular weight was associated with fewer Sertoli cells, spermatogonia, spermatocytes, elongated spermatids, and epididymal spermatozoa. However, Leydig cell number and the concentration of serum testosterone were equivalent between Irs2-deficient and control males. Testicular weight was reduced similarly in non-diabetic and diabetic Irs2 −/− mice, indicating that hyperglycemia does not compound the effects of Irs2 deletion on impaired testis development. Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development.

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Section: Discussionsupporting

confidence: 52%

Insulin Receptor Substrate 2 Is Required for Testicular Development

2013

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“…Previous data from our laboratory showed that IRS2 mRNA was present in murine kidney at higher levels than in metabolic tissues such as liver . In contrast, IRS1 mRNA levels were similar in mouse liver and kidney, but were modestly up‐regulated in Irs2 −/− kidney extracts (data not shown).…”

Section: Resultsmentioning

confidence: 68%

“…Detection of IRS2 protein in mouse kidney extracts was difficult using available antibodies, and required immunoprecipitation to enrich for IRS2 . Immunohistochemistry using available antibodies did not identify specific IRS2 staining in discrete mouse kidney regions or cell types (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…For example, mice lacking IRS1 display reduced body size and mild insulin resistance, whereas Irs2 −/− mice are of normal size but are profoundly diabetic due to pancreatic β‐cell failure and hepatic insulin resistance . Studies have highlighted roles for IRS proteins in the kidney, with Irs2 −/− mice displaying altered insulin‐stimulated bicarbonate re‐absorption and also reduced kidney size and altered Akt → glycogen synthase kinase‐3 beta signalling . At the level of the glomerulus, insulin signalling in the podocyte is critical for normal kidney function, and mice lacking the insulin receptor in the glomerular podocytes develop albuminuria and glomerulosclerosis in the absence of hyperglycemia .…”

Section: Introductionmentioning

confidence: 99%

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Insulin receptor substrate‐2 is expressed in kidney epithelium and up‐regulated in diabetic nephropathy

et al. 2013

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Diabetic nephropathy (DN) is a progressive fibrotic condition that may lead to end-stage renal disease and kidney failure. Transforming growth factor-β1 and bone morphogenetic protein-7 (BMP7) have been shown to induce DN-like changes in the kidney and protect the kidney from such changes, respectively. Recent data identified insulin action at the level of the nephron as a crucial factor in the development and progression of DN. Insulin requires a family of insulin receptor substrate (IRS) proteins for its physiological effects, and many reports have highlighted the role of insulin and IRS proteins in kidney physiology and disease. Here, we observed IRS2 expression predominantly in the developing and adult kidney epithelium in mouse and human. BMP7 treatment of human kidney proximal tubule epithelial cells (HK-2 cells) increases IRS2 transcription. In addition, BMP7 treatment of HK-2 cells induces an electrophoretic shift in IRS2 migration on SDS/PAGE, and increased association with phosphatidylinositol-3-kinase, probably due to increased tyrosine/serine phosphorylation. In a cohort of DN patients with a range of chronic kidney disease severity, IRS2 mRNA levels were elevated approximately ninefold, with the majority of IRS2 staining evident in the kidney tubules in DN patients. These data show that IRS2 is expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP7 in the kidney. The specific up-regulation of IRS2 in the kidney tubules of DN patients also indicates a novel role for IRS2 as a marker and/or mediator of human DN progression.

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“…In the kidney, IRS2 plays a major role in insulin stimulation of renal proximal tubular transport and Akt phosphorylation in vitro [19]. A recent study identified a novel role for IRS2 in renal development and in the regulation of Akt signalling in the kidney [20]. FoxO3a, a member of the Forkhead family of transcription factors, has been identified as a major effector of TGF‐β1 [21].…”

Section: Introductionmentioning

confidence: 99%

Insulin receptor substrate 2 and FoxO3a signalling are involved in E‐cadherin expression and transforming growth factor‐β1‐induced repression in kidney epithelial cells

et al. 2011

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Insulin receptor substrate (IRS) proteins comprise a family of adaptor molecules that integrate extracellular signals from insulin and other ligands to intracellular effectors such as phosphoinositide 3-kinase and mitogenactivated protein kinase. The predominant forms of IRS protein in humans, IRS1 and IRS2, are widely expressed. Despite structural similarities, IRS1 and IRS2 display distinct signalling modalities, and mice lacking these proteins present with distinct phenotypes. Transforming growth factor (TGF)-b1 is the primary cytokine shown to induce epithelial-mesenchymal transition. Recent data have demonstrated a role for IRS1 in TGFb1-induced epithelial-mesenchymal transition in lung epithelial cells. In the present study, we report data showing that TGF-b1 signals via IRS2 in kidney epithelial cells. Small interfering RNA (siRNA)-mediated targeting of IRS2 increased E-cadherin expression, although it did not alter TGF-b1-mediated E-cadherin repression. Phosphorylation of the downstream target of IRS2 ⁄ Akt signalling, FoxO3a, was induced on Ser253 and, to a lesser extent, on Thr32. Transfection of FoxO3aThr32Ala mutant for 24 h greatly reduced FoxO3a phosphorylation on Ser253 but over-expression of FoxO3a Ser253Ala did not effect Thr32 phosphorylation, suggesting that a distinct order of phosphorylation of FoxO3a is required for physiological function in cells. Transfection of FoxO3a Ser253Ala mutant partially inhibited TGF-b1-mediated E-cadherin repression at 24 h. Taken together, these data highlight novel roles for IRS2 and FoxO3a in the regulation of kidney epithelial cells by E-cadherin.

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Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β?

Cited by 18 publications

References 45 publications

Insulin Receptor Substrate 2 Is Required for Testicular Development

Insulin Receptor Substrate 2 Is Required for Testicular Development

Insulin receptor substrate‐2 is expressed in kidney epithelium and up‐regulated in diabetic nephropathy

Insulin receptor substrate 2 and FoxO3a signalling are involved in E‐cadherin expression and transforming growth factor‐β1‐induced repression in kidney epithelial cells

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