Endothelium-derived relaxing factor (EDRF), chemically similar to identical to nitric oxide, helps maintain normal blood pressure by dilating blood vessels. L-arginine, the synthetic precursor of EDRF, normalizes blood pressure in the Dahl salt-sensitive rat model of hypertension, suggesting that defects in EDRF signalling could lead to hypertension. Recent studies have shown that EDRF not only modulates renal hemodynamics, but also alters renal sodium excretion. this provides another mechanism by which defects in EDRF signalling could lead to hypertension. However, the cellular origins of the EDRF signal, and the roles of EDRF in salt transport are unknown. EDRF receptors are heterodimeric soluble guanylyl cyclases. Two subunits (alpha1 and beta1) are widely distributed, presumably in blood vessels where they mediate vasodilation. Recently, a new soluble guanylyl cyclase subunit (beta2) was found which is preferentially expressed in the kidney. Its exact location and function are unknown. the long term goal of this project is to determine the role of EDRF in renal salt and water transport. We will investigate the following aims:
In Aim 1, we will localize and characterize the EDRF receptors to specific portions of the nephron and renal vasculature using assays for both cGMP accumulation and mRNA expression in microdissected tubules and blood vessels.
In Aim 2, we will localize the sites of EDRF production using isolated tubules and blood vessels. We will determine if EDRF is involved in intra- or inter- cellular communication.
Aim 3 will address the sites at which EDRF modulates sodium and water transport in in vitro isolated perfused tubules. We will determine which membrane and which transporter is the affected target.
In Aim 4, we will clone, express, and pharmacologically characterize other EDRF receptor subunits expressed in the kidney. We have preliminary evidence that alpha1 and beta1 are expressed in the renal vasculature, while only beta2 is expressed in renal tubules. Since EDRF receptors are heterodimers, this suggests the existence of a new EDRF receptor subunit (alphax). More complete knowledge of the EDRF pathway may allow the development of new therapies for hypertension.
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