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

Hookham, Michelle B.; O'Donovan, Helen; Church, Rachel H.; Mercier-Zuber, Annie; Luzi, Lucilla; Curran, Simon P.; Carew, Rosemarie M.; Droguett, Alejandra; Mezzano, Sergio; Schubert, Markus; White, Morris F.; Crean, John; Brazil, Derek P.

doi:10.1111/febs.12305

Cited by 20 publications

(16 citation statements)

References 61 publications

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“…While IRS1 expression and phosphorylation are normal [198] or reduced [199], IRS2 has normal levels in diabetes models [27,191]. IRS2 expression is preserved in the renal cortex of insulinresistant patients [191] or even enhanced in tubules of patients with diabetic nephropathy [200]. These findings corroborate the renal insulin resistance hypothesis as well as a site-specific and selective resistance.…”

Section: Glucose Effects On Renal Glucosesupporting

confidence: 67%

“…It was reported that insulin raises SGLT2 protein availability and activity independently of glucose and additionally regulates SGLT2i bioavailability [140][141][142]. Differences in IRec density along the nephron [46] and in the type of IRS expressed in diverse tubule segments, or the same segment but under distinct insulin sensitivity [27,191,[199][200][201]203], point to a renal site-specific selective insulin action and, possibly, to a spatial selective insulin resistance.…”

Section: Summary Of Evidence and Discussionmentioning

confidence: 99%

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Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Moreira

Muscelli

2020

Journal of Diabetes Research

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Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.

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Section: Glucose Effects On Renal Glucosesupporting

confidence: 67%

Section: Summary Of Evidence and Discussionmentioning

confidence: 99%

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Moreira

Muscelli

2020

Journal of Diabetes Research

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“…Insulin and IGF-1 signaling through IRS2 coordinates life span extension, metabolic regulation and cognition [33]. In the kidney, it has been shown that IRS2 is expressed in the tubules and increases in diabetes [34]. We now demonstrate that within the glomerulus IRS2 is also enriched in the podocyte compartment which constitutes approximately 10% of total glomerular cells [35].…”

Section: Discussionmentioning

confidence: 51%

“…Based on these and previous findings, we conclude that IRS2 has differential functions in different parts of the kidney. In the tubules it modulates renal fibrosis during DN [34,52], and in the podocyte it is important for insulin sensitivity, glucose uptake and cytoskeleton function. Similarly, differing roles of mTORC1 between the glomeruli and tubules in DN have also been reported [53,54].…”

Section: Discussionmentioning

confidence: 99%

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Santamaría¹,

Márquez²,

Lay³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2(-/-)). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2(-/-) podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2(-/-) podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

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“…These cytokines increase inhibition of IRS-mediated kinase activation; which can lead to disruption of insulin-dependent glucose uptake and may cause insulin resistance [48, 49]. In a study conducted in 2013, the expression of IRS2 in renal epithelial cells and up regulation of it in patients with diabetic nephropathy was shown [50]. Insulin resistance and its mediated type 2 diabetes and finally diabetic nephropathy have been reported in SLE [51, 52].…”

Section: Discussionmentioning

confidence: 99%

MiRNA and mRNA Profiling in Systemic Lupus Reveals a Novel Set of Cytokine - Related miRNAs and their Target Genes in Cases With and Without Renal Involvement

Ghods

Sarikaya

Arda

et al. 2017

Kidney Blood Press Res

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Background/Aims: MiRNAs transpire as promising elements in molecular medicine for the identification of new diagnostic, prognostic and targeting therapeutic biomarkers. This study consisted of four steps: First, to investigate one or a group of specific diagnostic miRNAs for Systemic Lupus Erythematosus (SLE) disease in patients with and without renal involvement, second, to identify cytokines genes’ expression profiling, third, comparing the profiles with related amounts in the serum and finally, to study target-gene-mediated functional roles of miRNAs, which have been correlated to disease development and progression. Methods: In order to use in microarray assays total RNA and miRNAs were isolated from blood and serum samples that were obtained from 16 SLE patients (9 with renal involvement and 7 without renal involvement). Taking coexistence of factors such as hypocomplementemia, positive ANA and anti-DNA into account, obtained data were processed. For each differentially expressed miRNA, potential target genes were predicted by microRNAorg, TargetScan and PITA prediction tools. Obtained mRNA profiling data were interrogated for the target genes. MiRNA and mRNA microarray results were confirmed by QRT-PCR. Finally, the amounts of cytokines were measured by multiplex ELISA method. Results: The results of study showed that among differentially expressed miRNAs in SLE patients with renal involvement compared to those without renal involvement, hsa-miR-766-3p, may play pivotal roles in PI3K-AKT-mTOR pathway. In addition according to the obtained data it is suggested that blood-borne proinflammatory cytokines such as IL-4, IL-6 and TNF-α alongside with disease stage and severity may contribute to this differential expression of these miRNA which may be leading to insulin resistance. Finally, hsa-miR-621, which was differentially expressed in hypertensive SLE patients without renal involvement and a positive ANA test with its predicted target gene “Kallikrein-related peptidase 9” may play a role in the pathophysiology of hypertension in SLE. Conclusions: We reported some human miRNAs which were differentially expressed in SLE patients according to disease activity and renal involvement. Larger studies are necessary to confirm our findings and detect further biomarkers.

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

Cited by 20 publications

References 61 publications

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

MiRNA and mRNA Profiling in Systemic Lupus Reveals a Novel Set of Cytokine - Related miRNAs and their Target Genes in Cases With and Without Renal Involvement

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