Grant: Operating Grant

Each human kidney contains 1 million tiny structures called glomeruli. The glomeruli filter the blood as the first step in its purification by the kidney. Two very important blood vessels, the afferent and efferent arterioles, control the inflow and outflow of blood to and from each glomerulus and control the filtration rate by regulating the pressure within the glomerular capillaries. When the afferent vessel constricts, glomerular pressure is reduced, whereas when the efferent arteriole constricts, glomerular pressure is increased. It is well appreciated that in the healthy kidney, the reactivity of these two vessels is independently controlled. For example, when blood pressure is reduced, dilation of the afferent arteriole and vasoconstriction of the efferent arteriole preserve kidney function by maintaining filtration pressure. In contrast, when blood pressure is increased, as in hypertension, a selective vasoconstriction of the afferent arteriole prevents injury to the glomerulus. We also know that diseases, including diabetes and chronic kidney disease (CKD), are associated with changes in the reactivity of the renal arterioles. Although these vessels are of obvious importance, little is known about the biochemical processes regulating their function. The reason for the lack of knowledge in this critical area is that it was not previously possible to perform such experiments. These vessels are exceedingly small (1/10th the size of a human eyelash) and are not readily accessible. We have developed methods to obtain individual afferent and efferent arterioles and to examine the key biochemical steps regulating vasoconstriction. The initial studies outlined in our proposal will define the differing biochemical pathways regulating function in the afferent and efferent arteriole and will provide a basis for subsequent studies determining how these mechanisms are altered in diabetes and CKD.