Altered expression and localization of insulin receptor in proximal tubule cells from human and rat diabetic kidney

Abstract

Diabetes is the major cause of end stage renal disease, and tubular alterations are now considered to participate in the development and progression of diabetic nephropathy (DN). Here, we report for the first time that expression of the insulin receptor (IR) in human kidney is altered during diabetes. We detected a strong expression in proximal and distal tubules from human renal cortex, and a significant reduction in type 2 diabetic patients. Moreover, isolated proximal tubules from type 1 diabetic rat kidney showed a similar response, supporting its use as an excellent model for in vitro study of human DN. IR protein down-regulation was paralleled in proximal and distal tubules from diabetic rats, but prominent in proximal tubules from diabetic patients. A target of renal insulin signaling, the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), showed increased expression and activity, and localization in compartments near the apical membrane of proximal tubules, which was correlated with activation of the GSK3β kinase in this specific renal structure in the diabetic condition. Thus, expression of IR protein in proximal tubules from type 1 and type 2 diabetic kidney indicates that this is a common regulatory mechanism which is altered in DN, triggering enhanced gluconeogenesis regardless the etiology of the disease.

SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice

“…This enzyme is a principal regulator of gluconeogenesis in the proximal tubule that is regulated at the mRNA level and upregulated in the diabetic kidney of rats and humans (9,10,21). This observed effect was specific for the diabetic kidney since empagliflozin did not affect the expression of PEPCK in WT kidneys.…”

“…PEPCK expression by proximal tubules is mainly downregulated by insulin and upregulated by glucagon, although its expression also increases during chronic acidosis as part of the pathway for generating ammonium and bicarbonate (10,21). The increase in PEPCK in Akita/ϩ was expected based on prior reports and known pathways (9,10,21). The mechanism whereby empagliflozin prevented this is not obvious.…”

(‐)‐Epicatechin and the Colonic 2,3‐Dihydroxybenzoic Acid Metabolite Regulate Glucose Uptake, Glucose Production, and Improve Insulin Signaling in Renal NRK‐52E Cells

“…Correspondingly, in preadipocytes oligomeric structures of a grape‐seed procyanidin extract activated IR by interacting with and inducing its tyrosine phosphorylation . In this line, a downregulation of IR and GSK3 has been reported in renal proximal tubules of diabetic rats, and a protective role for GSK3 has been suggested in high glucose‐treated renal proximal tubular cells . Moreover, it has been shown that the SGLT‐2‐mediated transport involved the phosphorylation of SGLT‐2 via IR signaling in HEK‐293T cells transfected with SGLT‐1 and ‐2, and in diabetic patients the administration of empagliflozin (an SGLT‐2 inhibitor) improved insulin secretion and peripheral glucose uptake through poorly defined mechanisms .…”

“…The modulation of IR and its downstream substrate IRS‐1 is essential for maintaining the glucose homeostasis, and constitute the first steps for recruiting and activating downstream pathways . To test the effect of EC and DHBA on tyrosine phosphorylation and total levels of IR and IRS‐1, NRK‐52E cells were exposed for 24 h to the previously mentioned concentrations of these compounds.…”

Associations between INSR and MTOR polymorphisms in type 2 diabetes mellitus and diabetic nephropathy in a Northeast Chinese Han population

“…INSR is involved in both adipogenesis and beta-cell insulin secretion, but may also be involved in type 2 diabetes mellitus (Brunetti et al, 2011). Furthermore, INSR expression in the kidney changes during diabetes (Gatica et al, 2013), suggesting that it is a factor contributing to the development of type 2 diabetic nephropathy.…”