Syed Khundmiri, Ph.D.
Numa P. G. Adams Bldg.
Laboratory Telephone: 202-806-4521/4522
B.Sc., Osmania University, Hyderabad, India (1988)
M.Sc., Aligarh Muslim University, Aligarh, India (1990)
Ph.D., Aligarh Muslim University, Aligarh, India (1996)
Postdoctoral Fellow, Owaisi Hospital and Research Center, Hyderaabad, India (1996-1999)
Postdoctoral Fellow, University of Louisville, (1999-2003)
Salt homeostasis in aging – Role of NHERF1 and Dopamine Receptors
Na-K ATPase regulation in renal proximal tubules
Role of V-ATPase in breast cancer metastasis
Grants and Funding
American Heart Association, Postdoctoral Fellowship, (2001-2003)
American Heart Association, Scientist Development grant, (2004-2008)
American Heart Association, Grant-in-Aid, (2009-2011)
NIH, National Institute of Aging, (2014-2016)
The major goal of my laboratory is to understand the role of NHERF1 in dopamine receptor sensitization and desensitization especially in renal proximal tubule. The long term goal of my laboratory is to understand the molecular mechanisms for regulation of sodium homeostasis in renal proximal tubules during aging and how this contributes to hypertension.
Hypertension in elderly patients reaches about 70%. Recent developments in the field have increased our ability to treat hypertension. However, there are many patients who do not respond to current treatments. Therefore, there is a strong need to understand the mechanisms of hypertension and in particular the mechanisms of salt sensitivity as it relates to hypertension in aging population. Salt homeostasis is maintained mainly by controlling salt reabsorption in the kidney through regulation of sodium transporters along the nephron. Sodium reabsorption is a secondary active transport process which utilizes the ability of Na-K ATPase (NKA) or the sodium pump to maintain intracellular sodium and potassium balance. In kidney epithelial cells, NKA is restricted to the basolateral membrane (BLM) where it provides the driving force for the vectorial transport of ions and solutes. Thus, NKA activity is a major regulator of sodium homeostasis and blood pressure control. Dopamine (DA) plays a major role in regulation of extracellular fluid volume and blood pressure control. DA acting through D1 like receptors (D1R and D5R) inhibits NKA and other sodium transporters like sodium hydrogen exchanger 3 (NHE3) to promote natriuresis. The action of DA is mediated through activation of both protein kinase A (PKA) and protein kinase C (PKC), through complementary and interdependent pathways, but the precise mechanisms are largely unknown. In aging rats DA fails to inhibit NKA and NHE3 in renal proximal tubules despite higher basal intrarenal DA production as compared to young animals. Prior studies showed that the expression of both D1R and NKA are decreased. Recent studies suggest that the loss of natriuretic response to DA and increased blood pressure in animal models of aging is due to D1R-G protein uncoupling mediated by phosphorylation of the receptor through G protein-coupled receptor kinase-4 (GRK4) dependent mechanisms. Using proteomics we identified that NHERF-1 co-immunoprecipitates with NKA and D1R and that this association is required for DA-mediated regulation of NKA. The D1R binds NHERF-1 through the PDZ-2 domain. The precise role of NHERF-1 in age-related changes in DA regulation of sodium transport has not heretofore been examined. The focus of my laboratory is to define the role of sodium-hydrogen exchanger regulatory factor -1 (NHERF-1) in DA-mediated inhibition of NKA in aging. NHERF-1 regulates several ion transporters including NKA and NHE3. Understanding the role of NHERF-1 expression in aging will be significant for understanding the mechanisms of DA-mediated natriuresis and hypertension. The immediate goal of my laboratory is to focus on postnatal expression of NHERF-1 and regulation in kidneys; whether NHERF-1 phosphorylation in response to DA changes during aging; and whether NHERF-1 acts as a modulator on NKA phosphorylation and assembles a signaling complex involving the NKA, D1R, and the PKCζ. The activation of D1R results in phosphorylation of NHERF-1 at Ser77 and Thr95 and Ser18 on NKA. Based on these studies and our data, we will address the hypothesis that “NHERF1 expression and/or phosphorylation is defective in aging resulting in failure of DA-mediated regulation of natriuresis”. Elucidating this control mechanism will advance our understanding of age-related hypertension.