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  • Kidney contributes importantly to the long term

    2024-02-23

    Kidney contributes importantly to the long-term blood pressure control via regulating sodium homeostasis. Renal proximal tubule (RPT) is one of the most critical segments for sodium reabsorption within kidney and therefore involved in blood pressure adjustment. This process is regulated by numerous hormones and humoral factors, including renin–angiotensin system (RAS) and insulin/insulin receptor. Angiotensin II (Ang II), as the major Bromfenac Sodium peptide of RAS, regulates sodium balance via two main receptor subtypes, angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R). AT1R and AT2Rs are expressed throughout the vascular and tubule sites in adult kidney. Stimulation of AT1R increases sodium (Na+) reabsorption in RPT and induces antinatriuresis. AT2R, as an antagonist of AT1R, can oppose or offset this action. Activation of AT2R decreases sodium reabsorption, induces natriuresis, maintains negative Na+ balance, and lowers blood pressure chronically in angiotensin-dependent hypertension via reducing Na+ reabsorption in RPT. Insulin/insulin receptor is another critical signaling pathway involved in sodium balance in RPT. Insulin receptor was expressed throughout the nephron. Studies have demonstrated that insulin/insulin receptor has the potential of increasing sodium retention through stimulating sodium transporters Na+-H+-exchanger and Na+-K+-ATPase in RPT. Some researches have been performed to elucidate the interaction between AT2R and insulin in different aspects. AT2R can impact the β-cell to α-cell ratio of the neonate islets, insulin secretory function, and the glucose tolerance in pups. Activation of AT2R leads to inhibition of insulin-induced extracellular signal-regulated protein kinase 2 (ERK2) activity and cell proliferation in transfected Chinese hamster ovary cells. In rat pheochromocytoma cell line, AT2R inhibits insulin-associated phosphoinositide 3-kinase and Akt phosphorylation and induces cell apoptosis. Although relationship between AT2R and insulin receptor has been revealed, the detailed mechanisms remain unclear. Both AT2R and insulin receptor exist in RPT and they execute the opposite functions in sodium metabolism, we presume that activation of AT2R inhibits insulin receptor in RPT. To confirm this hypothesis, we explored the interaction between AT2R and insulin receptor in RPT cells from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). We found that activation of AT2R was capable of decreasing insulin receptor expression and function in RPT cells from WKY rats, whereas this inhibitory effect was disturbed in RPT cells from SHRs. We suggested that an aberrant interaction between AT2R and insulin receptor may play an important role in the abnormal regulation of sodium excretion and consequently be implicated in hypertension.
    Methods
    Results
    Discussion The present study for the first time demonstrated that there is a link between AT2R and insulin receptor in RPT cells. AT2R is capable of inhibiting insulin receptor expression via PI3K and PKC pathways in RPT cells from WKY rats. Correspondingly, activation of AT2R in WKY cells reduces the insulin-mediated stimulatory effect on Na+-K+-ATPase activity, whereas this repression effect of AT2R on insulin receptor was aberrant in SHR cells. Altered interaction between AT2R and insulin receptor may contribute to the pathogenesis of hypertension. RAS is one of the major regulatory systems in the modulation of cardiovascular and renal function. Ang II, the primary RAS effector peptide hormone, executes multiple physiological or pathological roles via binding to different receptor subtypes, including AT1R and AT2R. Studies have shown that AT1R predominately mediates Ang II–induced vasoconstriction, sympathetic nervous system activation, inflammation, sodium reabsorption in RPT, and aldosterone secretion. AT2R is antagonistic to the above effects under most circumstances. Kemp et al have demonstrated that AT2R activation initiates its translocation to the RPT apical membrane. Intrarenal AT2R activation prevents Na+ retention and lowers blood pressure in Ang II–dependent hypertension. Ali et al found that AT2R activation shifts the abnormal regulation of AT1R and Angiotensin-converting enzyme 2 (ACE2) which contributes to obesity-related hypertension. AT2R activation also prevents salt-sensitive hypertension in the obese Zucker rat model of obesity and the metabolic syndrome.