Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

Abstract

Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCζ) inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway.

High glucose reduces megalin-mediated albumin endocytosis in renal proximal tubule cells through protein kinase B O-GlcNAcylation

“…They observed a decrease in megalin expression leading to a decrease in PT albumin reabsorption. In addition, it has been shown that PT PKB activity is inhibited in the streptozotocininduced diabetes animal model (49). Here, we observed that HG decreases megalin expression and albumin uptake and inhibits PKB activity in LLC-PK1 cells.…”

Prebiotic prevents impaired kidney and renal Oat3 functions in obese rats

“…Moreover, the decreased function of Oat3 is also regulated by insulin signaling. Our previous study in streptozotocin-induced diabetic rats showed that impaired insulin signaling affected a decrease in Oat3 function and that insulin treatment could restore this alteration (Lungkaphin et al 2014). From the results above, it could be summarized that renal RAS activation and insulin resistance in obesity led to the phosphorylation of PKCα and then induced NOX activity and Oat3 internalization (Fig.…”

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

“…Furthermore, glucose seems to amplify membrane SGLT2 protein availability in these cultures [22]. 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.…”

“…OAT type 3 (OAT3), through its colocalization with SGLT2 but not with SGLT1, enhanced the empagliflozin glycosuric effect [140]. The insulin effect raising [141] and the insulin resistance decreasing [142] renal OAT3 activity on the renal cortex suggest a link between insulin action and pharmacological inhibition of SGLT2. Indeed, a better understanding of insulin effects on tubular glucose transport and its interaction with SGLTi is imperative.…”