Insulin is the central hormone involved

Insulin is the central hormone involved in the control of glucose and lipid metabolism. Other nonmetabolic effects of insulin are intensively studied as well. Activation of insulin receptor not only promotes glucose uptake, protein synthesis, and inhibits lipid metabolism, but also is crucial for renal function in glomeruli and tubules. Insulin receptor has been shown regulating sodium excretion in RPTs. Studies supported that renal-specific knockout of insulin receptor in mice results in impairment of sodium transport and increased blood pressure. Our previous study has found that insulin increased Na+-K+-ATPase activity in RPTs. When signaling is aberrant here, as may occur in insulin-resistant states, it may be responsible for a number of important renal complications including hypertension. As two pivotal regulators in the regulation network of blood pressure, the cross talk between RAS and insulin has been described in many models. For example, Ang II can decrease the number of insulin receptors in the membrane in bovine aortic endothelial cells. Ang II leads to phosphorylation of insulin receptor substrates at Ser636/639 through activating mTOR/p70S6K and inhibits the insulin-stimulated phosphorylation of eNOS via AT1R. Insulin-induced capillary recruitment is abrogated, and glucose disposal is attenuated after the treatment with AT2R antagonist, PD123319. However, correlation between AT2R and insulin receptor on sodium transport in kidney remains undetermined. Our current study showed that AT2R agonist CGP42112 decreased insulin receptor mRNA and protein expressions in a concentration- and time-dependent manner in WKY rats RPT cells. Pretreatment with the AT2R agonist decreased the stimulatory effect of insulin on Na+-K+-ATPase activity in RPT AG-490 from WKY rats. Therefore, we deduced that AT2R depresses the function of insulin receptor via inhibiting insulin receptor expression. Balance between AT2R and insulin receptor is important to keep the steady state for sodium reabsorption in the proximal tubule. However, the antagonism of AT2R on insulin receptor is lost in RPT cells from SHRs. Early studies have proved that WKY and SHRs RPT cells own different ways of physiological regulation. There are different responses even to the same treatment in WKY rats and SHRs. For example, intravenous infusion of losartan for 1 week significantly lowered systolic blood pressure and increased urine volume and sodium excretion in D4 dopamine receptor agonist treated SHRs, but not in WKY rats. We showed here that there was an aberrant regulation of AT2R on insulin receptor in SHRs which might be involved in the pathogenesis of hypertension. The mechanism for the inhibitory effect of AT2R on insulin receptor expression in WKY rats was further investigated in this study. Both PKC and PI3K play important roles in the signal transduction in inhibition of AT2R on insulin receptor. Previous studies show that the signaling pathway for RAS and insulin involves the activation of PI3K and PKC. AT2R can inhibit the phosphorylation and the signal transduction of PKC. A previous study has found that inhibition of PKC prevents hepatic insulin resistance. Similarly, mutation or knockout of PKC can change the insulin sensitivity or insulin receptor phosphorylation. The present study showed that the inhibitory effect of AT2R on insulin receptor expression was blocked by PKC or PI3K inhibitor in WKY RPT cells, but not in SHR RPT cells, indicating that PKC and PI3K are involved in this signaling pathway in normotensive states, but not in hypertensive states. Besides insulin receptor protein expression, mRNA level was also decreased by stimulating AT2R in WKY RPT cells, indicating that the regulation may occur at the transcriptional level. However, the detailed mechanisms remain to be elucidated in the future. In summary, we have demonstrated that AT2R inhibits insulin receptor expression in WKY cells, while increases it in SHR cells. PKC and PI3K are signaling pathways involved in the regulation of AT2R on insulin receptor in WKY cells, but not in SHR cells. The regulation is pathophysiological significance because pretreatment with CGP42112 inhibited the insulin-mediated stimulatory effect on Na+-K+-ATPase activity or ERK1/2 phosphorylation in WKY RPT cells but increased it in SHR RPT cells.