application) The overall objective is to determine the mechanisms involved in the short-term and long-term regulation of sodium transport in the kidney by dopamine. The D1-receptor-regulated sodium transport is mediated by protein kinase A (PKA) and protein kinase C (PKC)-dependent and -independent mechanism. Furthermore, a G-protein-coupled receptor kinase, GRK4, is selectively expressed in renal tubules and is the GRK isoform that regulates renal tubular D1 receptor function.
The specific aims are : 1) To test the hypothesis that G-protein beta/gamma subunits directly or indirectly modulate the D1 receptor/GSalpha-mediated inhibition of luminal NHE activity (in proximal tubules and medullary thick ascending limb of Henle), the applicants will determine G protein subunit expression in nephron segments and the role of beta/gamma subunits on second messenger independent-regulated sodium transport, 2) To test the hypothesis that D1 receptors decrease sodium transport in renal proximal tubules by inhibition of luminal NHE and basolateral Na+/K+ATPase activity in a time-dependent manner, they will determine in immortalized rat renal proximal tubule cells the effects of D1 receptors on NHE and Na+/K ATPase activity and expression. This will determine if the longer-term inhibition of luminal and basolateral sodium transport by D1 receptors is due to transcriptional regulation of NHE and Na+/K+ ATPase, 3) To test the hypothesis that the time-dependent effects of D1 receptors on sodium transport in rat renal proximal tubules are mediated by D1 receptor-regulated second messengers in a time-dependent manner, they will measure the effects of D1 receptor stimulation on PKA and PKC activity and their roles on the short- and long-term regulation of D1 receptor function, and 4) To test the hypothesis that GRK4 specifically regulates D1 receptors, they will determine the specificity of the linkage of GRK4 and the expression and function of the two D1-like receptors, D1A and D1B, in specific nephron segments. Studies on the mechanisms involved in the D1-receptor regulation of sodium transport are important since an abnormality in the regulation of the D1A receptor gene is involved in the pathogenesis of hypertension.
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