Adenosine regulates several physiological systems mediated by 4 distinct receptors: A1, A2a, A2b and A3. Activation of A1 receptors (A1-AR) in the afferent arterioles (AA) increases AA resistance and reduces the glomerular filtration rate (GFR). A1-ARs in epithelial cells of the nephron mediate sodium and fluid reabsorption and are implicated in normal homeostatic function, yet their role in nephron function is poorly understood. This study proposes that A1-ARs mediate an important intrarenal regulatory system in the proximal tubule (PT), glomerulotubular balance (GTB). The hypothesis is that adenosine produced locally in the PT regulates fluid and electrolyte reasborption through activation of A1-AR in response to changes in fluid delivery and thereby mediates GTB.
Specific aim one will evaluate the regulation of the expression of A1-AR in the PT in response to various salt intakes and to angiotensin II infusions. Expression of the sodium hydrogen exchanger 3 (NHE3), the major Na entry mechanism in the epithelial cells of PT, and other related proteins will also be measured and correlated to changes in A1-AR expression. In the second aim, GTB will measured by direct microperfusion of the PT with agents that inhibit and activate A1-ARs. In addition, the GTB functional responses to changes in salt intake, long term angiotensin II treatment and acute inhibition of angiotensin receptors will be measured. The roles of possible mediators of the link between A1-AR and Na/fluid reabsorption will be assessed. These include, NHE3, phosphokinase C, G protein and others. The direct actions of drugs, on PT function rather than whole kidney function will be evaluated. These studies combining renal microperfusion and micropuncture with molecular and pharmacological tools to evaluate the role of A1-AR in the PT should lead to greater understanding of the regulatory role of adenosine in the kidney. These studies are timely, since recent clinical trials on A1-AR antagonists report increased diuresis and natriuresis while preserving GFR, consistent with a PT effect.
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