The role of insulin in controlling sodium (Na+) reabsorption in the kidney is of particular clinical importance due to its relevance to hypertension associated with the metabolic (insulin resistance) syndrome. Hyperinsulinemia can lead to inappropriate renal Na+ handling, resulting in hypertension. A major site of insulin's action is on the epithelial Na+ channel (ENaC) found in the aldosterone-sensitive distal nephron. Insulin, through the phosphatidylinositide 3'-kinase (PI3K) signaling pathway, activates serum and glucocorticoid regulated kinase 1 (SGK1), which plays a key role in stimulating ENaC accumulation at the apical membrane of the principal cell. SGK1 appears to have a novel lipid interaction motif (PXL domain) that may participate in SGK1 activation by insulin. The broad objective of this proposal is to elucidate the mechanistic basis of how SGK1 is activated by the insulin-PI3K signaling pathway.
The aims are the following: (1) Identify which phosphoinositides are functionally important for SGK1's ability to stimulate ENaC transport; (2) Evaluate whether the PXL domain is required for SGK1 activation; (3) Determine whether the PXL domain regulates SGK1 activation through membrane targeting. The elucidation of these pathways will likely identify novel avenues of treatment for this form of hypertension, which will undoubtedly become more prevalent with the rising obesity epidemic in our country. In addition to the proposed experiments, didactic coursework in biochemistry, cell biology, and the responsible conduct of research will complement a structured research training program to assist the candidate in achieving his long term goal for an academic career as a physician-scientist in nephrology. Dr. David Pearce, who is a leader in the field of hormone regulation of ion transport, will mentor the candidate's scientific development. Moreover, Dr. Stephen Gluck, a highly respected expert in cellular physiology of ion transporters, and Dr. Keith Mostov, and internationally recognized expert in epithelial cell trafficking, will provide scientific expertise in the design of experiments and interpretation of results. A professional development advisory committee will also convene at regular intervals to provide scientific and career support. UCSF offers the scientific expertise and the technical resources to provide an ideal environment for preparing this candidate for a successful career as a physician-scientist.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK073487-01
Application #
7023243
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$121,450
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rajagopal, Madhumitha; Thomas, Sheela V; Kathpalia, Paru P et al. (2014) Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells. Am J Physiol Cell Physiol 306:C263-78
Rajagopal, Madhumitha; Kathpalia, Paru P; Widdicombe, Jonathan H et al. (2012) Differential effects of extracellular ATP on chloride transport in cortical collecting duct cells. Am J Physiol Renal Physiol 303:F483-91
Rajagopal, Madhumitha; Kathpalia, Paru P; Thomas, Sheela V et al. (2011) Activation of P2Y1 and P2Y2 receptors induces chloride secretion via calcium-activated chloride channels in kidney inner medullary collecting duct cells. Am J Physiol Renal Physiol 301:F544-53
Thomas, Sheela V; Kathpalia, Paru P; Rajagopal, Madhumitha et al. (2011) Epithelial sodium channel regulation by cell surface-associated serum- and glucocorticoid-regulated kinase 1. J Biol Chem 286:32074-85
Kathpalia, Paru P; Charlton, Carol; Rajagopal, Madhumitha et al. (2011) The natriuretic mechanism of Gamma-Melanocyte-Stimulating Hormone. Peptides 32:1068-72
Pao, Alan C; Bhargava, Aditi; Di Sole, Francesca et al. (2010) Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney. Am J Physiol Renal Physiol 299:F1496-506
Rajagopal, Madhumitha; Pao, Alan C (2010) Adenosine activates a2b receptors and enhances chloride secretion in kidney inner medullary collecting duct cells. Hypertension 55:1123-8
Pao, Alan C; McCormick, James A; Li, Hongyan et al. (2007) NH2 terminus of serum and glucocorticoid-regulated kinase 1 binds to phosphoinositides and is essential for isoform-specific physiological functions. Am J Physiol Renal Physiol 292:F1741-50
Bhalla, Vivek; Soundararajan, Rama; Pao, Alan C et al. (2006) Disinhibitory pathways for control of sodium transport: regulation of ENaC by SGK1 and GILZ. Am J Physiol Renal Physiol 291:F714-21