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One of the tenants of renal physiology is that increases in renal perfusion pressure (blood pressure) result in increased excretion of sodium and water. This phenomenon is known as the renal pressure-natriuresis relationship. Interestingly, in all animal models of hypertension tested, the relationship between increases in renal perfusion pressure and sodium and water excretion is altered so that hypertensives require higher levels of renal perfusion pressure to excrete normal amounts of sodium and water as compared to individuals with normal blood pressure. My lab has been studying the relationship between several hormone systems and the regulation of renal pressure-natriuresis in hypertension. Currently, we are focused on the heme oxygenase system and its metabolites in modifying the renal pressure-natriuresis relationship in hypertension. Heme oxygenase (HO) is an enzyme responsible for the breakdown of heme into biliverdin, carbon monoxide (CO), and free iron. Biliverdin is then reduced to bilirubin by the enzyme biliverdin reductase as outlined in the figure below.
Heme oxygenase enzymes are found in two major forms. HO-1 is the inducible isoform of HO. HO-1 can be induced by several physiological and pathophysiological stimuli including: hypoxia, ischemia, exposure to nephrotoxins, and in response to inflammation. HO-2 is the constitutive express isoform of HO that is expressed in low levels in most tubule and vascular structures of the kidney. My lab has been interested in the renal mechanisms that mediate the antihypertensive actions of HO-1 induction in the kidney. Our group first reported that kidney specific induction of HO-1 was able to reduce blood pressure in a model of angiotensin (Ang) II-dependent hypertension. We have recently created a novel transgenic mouse model in which the HO-1 isoform is expressed specifically in thick ascending loop of Henle (TALH) cells in the kidney. We have demonstrated that these mice exhibit a lower blood pressure after infusion of Ang II. Interestingly, these mice exhibit decreased levels of the Na, K, 2Cl (NKCC2) transporter in the kidney. We are currently performing experiments to determine the regulation of the NKCC2 transporter by HO-1 and its metabolites. We are also developing both kidney specific overexpression models in nephron segments such as the proximal tubule, and collecting duct to determine the effects of increased levels of HO-1 in these nephron segments on sodium reabsorption and blood pressure. In addition, we have received mice which contain a conditional knockout allele of HO-1 and are developing mice with kidney tubule segment specific deficiency in HO-1 to understand the role of endogenous HO-1 and its metabolites in the regulation of sodium reabsorption and blood pressure.
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