Renal hemodynamics and excretory function in health and disease
My research interests are focused on kidney function, specifically the maintenance of body fluid homeostasis and blood pressure control. The excretion rates of water and solutes by the kidneys must be in balance with the intake, or metabolic production, of these substances so that the composition of body fluids remains stable. This balance is achieved by hormonal and neuronal inputs to the kidney that regulate all aspects of renal function, predominantly the rate of blood flow through the kidneys, the rate of filtration of plasma into the renal tubules, and the subsequent actions of the renal tubules to convert this plasma ultrafiltrate into final urine. I have been engaged in the study of a potential link between the intestines and the kidney in which intestinal peptides are released into the circulation after salt intake in order to increase sodium excretion in the urine. We have discovered that the peptide prouroguanylin is released in this way and is converted into the active peptide after filtration into the renal tubules. However, the system is complicated by the fact that prouroguanylin stimulates more salt excretion than uroguanylin and we have identified a novel peptide fragment from the prosequence that provides the explanation for this unexpected finding.
Most recently, I have begun to investigate the role of an ectoenzyme, ADP ribosyl cyclase, also known as CD38, in the regulation of renal blood flow. CD38 acts to convert nicotinamide adenine dinucleotide (NAD) into cyclic ADP ribose (CADPR) which is now known to be an important second messenger in the contractile response of vascular smooth muscle cells. The importance of CD38 in the kidney is evident from the renal vascular responses in knockout mice that have the CD38 gene deleted; these animals have a significantly diminished vasoconstrictor response to vasoconstrictor agents such as angiotensin II. The research into this system will identify the molecular pathways used by CADPR to modulate the contractile response of smooth muscle, and the ways in which regulation of CD38 activity is integrated into the control of renal blood flow.
Finally, I am engaged in an investigation into the redistribution of blood flow within the kidney during renal failure. Within the kidney, large differences in regional blood flow are present that support the diverse functional responsibilities of each region. These flow patterns become disrupted in diseased kidneys, leading to functional derangements and tissue damage when fragile filtering units become exposed to excessive blood pressure. Measurements of the regional differences in blood flow have been extremely hard to measure but recently, the application of contrast enhanced ultrasound imaging has allowed us to measure blood flow non–invasively within kidney regions. We are using this technique to follow changing patterns in intrarenal blood flow during the development of renal failure in rats. This will allow us to characterize these changes for the first time and to develop monitoring procedures that will allow us to evaluate the effectiveness of treatment strategies designed to slow the progression of renal failure and, hence, preserve renal function.