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Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells.

ABSTRACT: Both renin-angiotensin systems and insulin participate in kidney-involved blood pressure regulation. Activation of angiotensin II type 2 receptor (AT2R) decreases sodium reabsorption in renal proximal tubule (RPT) cells, whereas insulin produces the opposite effect. We presume that AT2R has an inhibitory effect on insulin receptor expression in RPT cells, which may affect renal sodium transport and therefore be of physiological or pathological significance. Our present study found that activation of AT2R inhibited insulin receptor expression in a concentration and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. In the presence of a protein kinase C (PKC) inhibitor (PKC inhibitor peptide 19-31, 10-6 mol/L) or a phosphatidylinositol 3 kinase inhibitor (wortmannin, 10-6 mol/L), the inhibitory effect of AT2R on insulin receptor was blocked, indicating that both PKC and phosphatidylinositol 3 kinase were involved in the signaling pathway. There was a linkage between AT2R and insulin receptor which was determined by both laser confocal microscopy and coimmunoprecipitation. However, the effect of AT2R activation on insulin receptor expression was different in RPT cells from spontaneously hypertensive rats (SHRs). Being contrary to the effect in WKY RPT cells, AT2R stimulation increased insulin receptor in SHR RPT cells. Insulin (10-7 mol/L, 15 minutes) enhanced Na+-K+-ATPase activity in both WKY and SHR RPT cells. Pretreatment with CGP42112 decreased the stimulatory effect of insulin on Na+-K+-ATPase activity in WKY RPT cells, whereas pretreatment with CGP42112 increased it in SHR RPT cells. It is suggested that activation of AT2R inhibits insulin receptor expression and function in RPT cells. The lost inhibitory effect of AT2R on insulin receptor expression may contribute to the pathophysiology of hypertension.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6389274 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells.

Yang Yang Y Chen Caiyu C Fu Chunjiang C Xu Zaicheng Z Lan Cong C Zeng Yongchun Y Chen Zhi Z Jose Pedro A PA Zhang Ye Y Zeng Chunyu C

Journal of the American Society of Hypertension : JASH 20171206 2

Both renin-angiotensin systems and insulin participate in kidney-involved blood pressure regulation. Activation of angiotensin II type 2 receptor (AT<sub>2</sub>R) decreases sodium reabsorption in renal proximal tubule (RPT) cells, whereas insulin produces the opposite effect. We presume that AT<sub>2</sub>R has an inhibitory effect on insulin receptor expression in RPT cells, which may affect renal sodium transport and therefore be of physiological or pathological significance. Our present stud ...[more]

PMID: 29289466

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Project description:The renin-angiotensin (Ang) system controls blood pressure, in part, by regulating renal tubular sodium transport. In the kidney, activation of the angiotensin II type 1 (AT(1)) receptor increases renal sodium reabsorption, whereas the angiotensin II type 2 (AT(2)) receptor produces the opposite effect. We hypothesized that the AT(2) receptor regulates AT(1) receptor expression and function in the kidney.In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto rats, CGP42112, an AT(2) receptor agonist, decreased AT(1) receptor mRNA and protein expression (P?<?0.05), as assessed by reverse transcriptase-polymerase chain reaction and immunoblotting. The inhibitory effect of the AT(2) receptor on AT(1) receptor expression was blocked by the AT(2) receptor antagonist, PD123319 (10?(-6)mol/l), the nitric oxide synthase inhibitor N(w)-nitro-L-arginine methyl ester (10(-4)?mol/l), or the nitric oxide-dependent soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10(-5)?mol/l), indicating that both nitric oxide and cyclic guanosine monophosphate (cGMP) were involved in the signaling pathway. Furthermore, CGP42112 decreased Sp1 serine phosphorylation and reduced the binding of Sp1 to AT(1) receptor DNA. Stimulation with Ang II (10(-11)?mol/l per 30?min) enhanced Na(+)-K(+)-ATPase activity in RPT cells, which was prevented by pretreatment with CGP42112 (10(-7)?mol/l per 24?h) (P?<?0.05). The above-mentioned results were confirmed in RPT cells from AT(2) receptor knockout mice; AT(1) receptor expression and Ang II-stimulated Na-K-ATPase activity were greater in these cells than in RPT cells from wild-type mice (P?<?0.05). AT(1)/AT(2) receptors co-localized and co-immunoprecipitated in RPT cells; short-term CGP42112 (10?mol/l per 30?min) treatment increased AT(1)/AT(2) receptor co-immunoprecipitation (P?<?0.05).These results indicate that the renal AT(2) receptor, via nitric oxide/cGMP/Sp1 pathway, regulates AT(1 )receptor expression and function, which may be important in the regulation of sodium excretion and blood pressure.

Dataset Information

Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells.

Publications

Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells.

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