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Insulin treatment enhances AT₁ receptor function in OK cells

Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas

Submitted 13 October 2003 ; accepted in final form 7 February 2005

Increased renal sodium retention is considered a major risk factor contributing to hypertension associated with chronic hyperinsulinemia and obesity. However, the molecular mechanism involved is not understood. The present study investigates the effect of insulin treatment on AT₁ receptor expression and ANG II-induced stimulation of Na/H exchanger (NHE) and Na-K-ATPase (NKA) in opossum kidney (OK) cells, a proximal tubule cell line. The presence of the AT₁ receptors in OK cells was confirmed by the specific binding of ¹²⁵I-sar-ANG II and by detecting 43-kDa protein on Western blot analysis with AT₁ receptor antibody and blocking peptide as well as by expression of AT₁ receptor mRNA as determined by RT-PCR. Insulin treatment (100 nM for 24 h) caused an increase in ¹²⁵I-sar-ANG II binding, AT₁ receptor protein content, and mRNA levels. The whole cell lysate and membrane showed similar insulin-induced increase in the AT₁ receptor protein expression, which was blocked by genistein (100 nM), a tyrosine kinase inhibitor, and cycloheximide (1.5 µg/ml), a protein synthesis inhibitor. Determination of ethyl isopropyl amiloride-sensitive ²²Na⁺ uptake, a measure of the NHE activity, revealed that ANG II (1–100 pM)-induced stimulation of NHE in insulin-treated cells was significantly greater than in the control cells. Similarly, ANG II (1–100 pM)-induced stimulation of ouabain-sensitive ⁸⁶Rb⁺ uptake, a measure of NKA activity in insulin-treated cells, was significantly greater than in the control cells. ANG II stimulation of both the transporters was blocked by AT₁ receptor antagonist losartan, suggesting the involvement of AT₁ receptors. Thus chronic insulin treatment causes upregulation of AT₁ receptors, which evoked ANG II-induced stimulation of NHE and NKA. We propose that insulin-induced increase in the renal AT₁ receptor function serves as a mechanism responsible for the increased renal sodium reabsorption and thus may contribute to development of hypertension in conditions associated with hyperinsulinemia.

angiotensin II; Na-K-ATPase; Na/H exchanger

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