Received December 28, 2006
Accepted on May 24, 2007

BASIC RESEARCH

Insulin Receptor Protein Abundance in the Kidney Is Reduced in Insulin-Resistant Rats and Upregulated by Candesartan

Swasti Tiwari ^*, Veerendra K.M. Halagappa ^*, Shahla Riazi ^*, Xinqun Hu ^*, and Carolyn A. Ecelbarger ^*1

*Division of Endocrinology and Metabolism, Department of Medicine, Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, DC

¹ To whom correspondence should be addressed. E-mail: st285{at}georgetown.edu.

	Abstract

Insulin in the kidney may have an unappreciated role in BP normalization. Immunoblotting was used to determine whether renal insulin receptor (IR) protein levels were altered in insulin-resistant rats and via which mechanisms. Obese Zucker rats had significantly decreased (42 to 70%) renal IR ( and subunits) in kidney cortex and outer and inner medulla relative to lean rats. In addition, they had significantly reduced phosphorylated IR- abundance in the inner medulla. Fisher 344 x Brown Norway (F1 hybrid) rats that were made mildly insulin-resistant by feeding of a high-fat (35%) diet also had 29 and 45% reduced inner medullary IR- and IR-, respectively, relative to rats that were fed control diets. Treatment of the insulin resistance in Zucker rats by chronic, daily administration of rosiglitazone partially restored renal IR levels. For elucidation of the mechanism(s) underlying decreased IR in insulin resistance, rats were administered an infusion of insulin or treated with streptozotocin for evaluation of hyperinsulinemia versus hyperglycemia. Rats that were administered an infusion of insulin did not have a decrease in renal IR; in fact, cortex and outer medullary IR- levels were increased (61 to 130%). Hyperglycemia, in contrast, did result in a 27 to 57% reduction in both IR- and IR-, suggesting a potential role for hyperglycemia in the downregulation. Finally, a role for the angiotensin II type 1 receptor in IR regulation was determined. Lean and obese Zucker rats that were treated with candesartan, an angiotensin II type 1 receptor antagonist, had a 40 to 41% increased IR- and 23 to 160% increased IR- abundance relative to untreated rats. Overall, downregulation of renal IR was demonstrated in insulin-resistant rats. Hyperglycemia and/or upregulation of angiotensin II activity may play an active mechanistic role.