Hyperinsulinemia has been linked to hypertension in both animals and humans. Furthermore, insulin has been shown to result in sodium retention by the kidney. In cell culture, insulin directly increases sodium transport capacity of the amiloride-sensitive sodium channel (ENaC), normally located in the renal connecting tubule and collecting duct. Inappropriate retention of sodium in the distal portion of the tubule could result in expanded extracellular fluid volume and hypertension. However, it is not clear what are direct versus indirect effects of hyperinsulinemia with regard to sodium balance. Furthermore, the impact of hyperinsulinemia on the expression and regulation of specific renal sodium transporters and/or channels has not been aqequately studied. Antibodies against many of these proteins have only recently become available. In this proposal, we plan to test the overall hypothesis that insulin and """"""""insulin sensitizing agents"""""""", such as PPAR-gamma agonists, will, as a whole, increase the protein abundances of several critical sodium transport proteins expressed in the kidney. We will examine both chronic and acute changes in the abundance and cellular location of these proteins by semi-quantitative immunoblotting and immunohistochemistry.
For specific aim 1, we plan to assess the direct effect of increased circulating insulin levels on the relative abundances of the two primary apical sodium transport proteins of the postmacula densa portion of the renal tubule: 1) the amiloride-sensitive epithelial sodium channel (ENaC); and 2) the thiazide-sensitive Na-CI cotransporter (NCC).
In specific aim 2, we will evaluate the correlation of changes in ENaC subunit and NCC protein abundances with changes in rat blood pressure, and sensitivity to transporter or channel selective diuretics, i.e., amiloride and polythiazide.
In specific aim 3, we will address candidate cellular mechanisms for the increase in ENaC subunit or NCC protein abundances observed with insulin infusion.
In specific aim 4 we will evaluate relative changes in cellular distribution of both NCC and ENaC subunits in response to acute and chronic insulin exposure. Finally, in specific aim 5, we will investigate the impact of dietary PPAR-gamma agonists on the regulation of all of the major renal sodium transporter proteins in normal rats and insulin resistant, obese Zucker rats. These studies will, hopefully, provide us with an enlightened understanding of the role of insulin in sodium balance.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Barouch, Winifred
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Georgetown University
Internal Medicine/Medicine
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Tiwari, Swasti; Li, Lijun; Riazi, Shahla et al. (2010) Sex differences in adaptive downregulation of pre-macula densa sodium transporters with ANG II infusion in mice. Am J Physiol Renal Physiol 298:F187-95
Klein, Janet D; Rash, Arjun; Sands, Jeff M et al. (2009) Candesartan Differentially Regulates Epithelial Sodium Channel in Cortex Versus Medulla of Streptozotocin-Induced Diabetic Rats. J Epithel Biol Pharmacol 2:23
Hu, Jun; Tiwari, Swasti; Riazi, Shahla et al. (2009) Regulation of angiotensin II type I receptor (AT1R) protein levels in the obese Zucker rat kidney and urine. Clin Exp Hypertens 31:49-63
Tiwari, Swasti; Li, Lijun; Riazi, Shahla et al. (2009) Sex and age result in differential regulation of the renal thiazide-sensitive NaCl cotransporter and the epithelial sodium channel in angiotensin II-infused mice. Am J Nephrol 30:554-62
Riazi, Shahla; Tiwari, Swasti; Sharma, Nikhil et al. (2009) Abundance of the Na-K-2Cl cotransporter NKCC2 is increased by high-fat feeding in Fischer 344 X Brown Norway (F1) rats. Am J Physiol Renal Physiol 296:F762-70
Song, J; Liu, H; Ressom, H W et al. (2008) Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis. Exp Clin Endocrinol Diabetes 116:315-25
Tiwari, Swasti; Sharma, Nikhil; Gill, Pritmohinder S et al. (2008) Impaired sodium excretion and increased blood pressure in mice with targeted deletion of renal epithelial insulin receptor. Proc Natl Acad Sci U S A 105:6469-74
Tiwari, Swasti; Blasi, Eileen R; Heyen, Jonathan R et al. (2008) Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats. Pharmacol Res 57:383-92
Madala Halagappa, Veerendra K; Tiwari, Swasti; Riazi, Shahla et al. (2008) Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat. Am J Physiol Renal Physiol 294:F1222-31
Riazi, Shahla; Madala-Halagappa, Veerendra K; Dantas, Ana Paula et al. (2007) Sex differences in renal nitric oxide synthase, NAD(P)H oxidase, and blood pressure in obese Zucker rats. Gend Med 4:214-29

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