Generation of mice with targeted disruption of the A1 adenosine receptor gene and their use in studies of renal function.

Abstract

Adenosine exerts a wide range of effects throughout the body, and these actions are mediated by four subtypes of adenosine receptors (A1, A2a, A2b and A3). Adenosine has been implicated to be a determinant of metabolic control of organ function. In the kidney, activation of A1 adenosine receptor (AJAR) in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region of the nephron. To further elucidate the role of AJAR in TGF and in other aspects of renal function, we have generated and studied mice in which the entire AJAR coding sequence was deleted by homologous recombination. We found there are no apparent gross anatomical abnormalities in A1AR-/- mice. Plasma and urinary electrolytes, arterial blood pressure, heart rates, and glomerular filtration rates were indistinguishable between A1AR+/+, A1AR+/-, and A1AR-/- mice. However, TGF responses were completely abolished in A1AR-/- mice. Absence of TGF responses in A1AR deficient mice suggests that adenosine is a required constituent of the juxtaglomerular signaling pathway. A1AR null mutant mice are a promising tool to study the functional role of A1AR in different target tissues.