Table 2.
Summary of data describing roles for IRS proteins in kidney function and diabetic nephropathy
| IRS protein involved | Rodent genotype/phenotype | Kidney region/cell affected | Main findings | Reference |
|---|---|---|---|---|
| IRS1 | OLETF rats that developed diabetes and overt nephropathy | Renal cortex | IRS1 protein expression significantly reduced vs control LETO rats | Nakamura et al (2015) [79] |
| IRS1 | ROP mice | Isolated mesangial cells | High glucose increased total IRS1 protein expression and IRS1 phosphorylation in mesangial cells from glomerulosclerosis-prone ROP mice, and levels of IGF-1 receptor and IGF-1 also increased. This is consistent with previous data implicating IRS1 as the main IRS protein involved in IGF-1 signalling. ROP mesangial cells expressed less IGFBP-2 vs control mice, and individuals with DN presented with reduced IGFBP-2 in glomeruli vs control individuals, indicating the potential for IGFBP-2 as a marker identifying patient susceptibility to DN. Low levels of IGFBP-2 may play a partial role in increased IGF-1 signalling via IRS1, as treatment of ROP mesangial cells with exogenous IGFBP-2 reduced glucose-induced increases in IRS1 phosphorylation, protecting cells from further damage | Fornoni et al (2006) [80]a; Myers et al (1993) [81] |
| IRS1 | NOD mice | Isolated mesangial cells | Mesangial cells from NOD mice (model of type 1 diabetes) with nephropathy displayed phenotypic changes such as IGF-1 signalling pathway activation | Fornoni et al (2006) [80] |
| IRS1 | db/db mice | Isolated mesangial cells | Mesangial cells from db/db mice (model of type 2 diabetes) also displayed phenotypic changes, such as IGF-1 signalling pathway activation | Fornoni et al (2006) [80] |
| IRS1 | C57BL/6 mice | Isolated mesangial cells | High glucose treatment of control mesangial cells from glomerulosclerosis-resistant C57BL/6 mice yielded changes that were similar to those observed with mesangial cells from NOD and db/db mice. These data suggest that both type 1 and type 2 diabetes stimulate the IGF-1 pathway | Fornoni et al (2006) [80] |
| IRS2 | Wild-type, Irs1 −/− and Irs2 −/− mice | Proximal tubule epithelial cells | Insulin-induced increases in tubular bicarbonate ion absorption and Akt phosphorylation were seen in wild-type mice, and this effect was decreased in Irs2 −/− mice. No defects in bicarbonate absorption were seen in Irs1 −/− mice, suggesting that IRS2 coordinates the effects of insulin upon tubular epithelial cell bicarbonate transport | Zheng et al (2005) [82] |
| IRS2 | Wild-type mice | Tubular epithelial cells | IRS2 expression detected in embryonic kidney tubules, adult proximal and distal tubules and cortical collecting duct. BMP-7 increased IRS2 signalling in HK-2 proximal tubule epithelial cells | Hookham et al (2013) [37] |
| IRS2 | Irs2 −/− mice | Podocytes | Irs2 −/− podocytes were found to be insulin resistant with respect to Akt signalling and GLUT4-mediated glucose uptake in response to insulin | Santamaria et al (2015) [36] |
aMouse- and human-based research summarised
DN, Diabetic nephropathy; IGFBP-2, IGF binding protein-2; LETO, Long–Evans Tokushima Otsuka (rats); OLETF, Otsuka Long–Evans Tokushima fatty (rats); ROP, ragged olygosyndactilism pintail (mice)