Cardiovascular-Kidney Interactions in Health and Disease Special feature : cardiovascular-kidney interactions in health and disease

THIS ISSUE CONTAINS 11 refereed manuscripts that describe work presented at the eighth Cardiovascular-Kidney Interactions in Health and Disease Meeting at Amelia Island Plantation, FL, on May 27–30, 2005. The three-day meeting featured original contributions on a broad range of topics including redox regulation and microvascular function, genetic and cellular regulation of vascular growth and function, and growing points in hypertension and cardiovascular disease. A central theme of many presentations was the emerging evidence for oxidative stress as a proximate step in the processes that lead to hypertension and cardiovascular-kidney damage. This topic has been reviewed recently (12). Twenty-four senior investigators participated. The meeting was funded by the Cardiovascular-Kidney Institute of Georgetown University (Washington, DC), the George E. Schreiner Chair of Nephrology at Georgetown University, and by generous educational grants from Pfizer (New York, NY), CV Therapeutics (Palo Alto, CA), Merck (Whitehouse Station, NJ), Amgen (Thousand Oaks, CA) and Novartis Pharmaceuticals (East Hanover, NJ). Although reactive oxygen species (ROS) have been implicated in the regulation of renal sodium transport (Na ) and in the pathogenesis of salt-sensitive hypertension, the mechanisms whereby superoxide (O2 ) regulates renal tubule transport remain unclear. O2 increases sodium chloride (NaCl) absorption in the thick ascending limb of Henle’s loop (THAL) in the absence of nitric oxide (NO), suggesting a direct effect on Na transport. The study of Juncos et al. (3) tested the hypothesis that the stimulatory effect of O2 on net NaCl absorption is due to increased Na /H exchange. They examined the effect of exogenous O2 on total, apical and basolateral Na /H exchange in isolated perfused THALs. Exogenous O2 was shown to stimulate apical Na /H exchange and inhibit basolateral Na /H exchange. This predicts that O2 enhances sodium bicarbonate (NaHCO3) absorption. Thus regulation of THAL Na/HCO3 absorption by O2 may underlie the pathogenesis of several forms of hypertension and acid/base disturbances. Magnesium (Mg ) is concentrated within cells where it regulates many enzymes. It can antagonize the effects of calcium and thereby may determine vascular smooth muscle cells (VSMCs) contraction/dilation. Depletion of cellular Mg increases vascular tone and reactivity, generates oxidative stress, and triggers vascular remodeling and hypertension. Recent findings have shown that the transient receptor potential melastins (TRPMs) 6 and 7 regulate Mg cellular influx. Therefore, the study by Touyz et el. (11) on the role of these proteins in ANG II-dependent Mg uptake by VSMCs is timely. TRPM7 expression is increased by ANG II in VSMCs from Wistar-Kyoto but not in spontaneously hypertensive rats (SHR), which also failed to increase intracellular Mg with ANG II. These studies suggest that TRPM7 is a critical mediator of cellular Mg homeostasis and its response to ANG II, which is modified in hypertension. Recent studies have characterized the interaction between dopamine and ROS. Activation of dopamine1 (D1)-like receptors (D1 and/or D5) induces an antioxidant response. Yang et al. (13) tested the hypothesis that stimulation of the D5 receptor inhibits NADPH oxidase activity and the production of ROS. They report that NADPH oxidase protein expression (gp91, p47, and Nox 4) and activity in kidney and brain, as well as plasma thiobarbituric acid-reactive substances (TBARs) were increased in D5 receptor-deficient (D5-/-) mice and that inhibition of NADPH oxidase with apocynin normalizes BP, renal NADPH oxidase activity, and plasma TBARs in these mice. They also report that stimulation of the D5 receptor in HEK-293 cells, which heterologously express human D5 receptor, decreases NADPH oxidase activity, expression of one of its subunits (gp91), and ROS production. Finally, they show that these effects of the D5 receptor on NADPH oxidase activity are independent of cAMP/PKA but are partially dependent on phospholipase D2. There is growing evidence of an important interaction between endothelin (ET) and sympathetic nerve activity (SNA). Recent studies by Dai et al. (1) suggest that ET may increase SNA in deoxycorticosterone acetate-salt hypertension through an action at endothelin-type BCETB receptors on cell bodies of postganglionic sympathetic neurons. To investigate the physiological relevance of these findings, Lau and colleagues (4) determined the role of ETB receptors in the in vivo increase in O2 in sympathetic ganglia. ETB receptor activation was shown to increase dihydroethidium oxidative fluorescence. They further tested whether increases in O2 could be attributed to elevated BP by responses to a pressor dose of phenylephrine. Their findings demonstrate in vivo that ETB receptor activation increases O2 in sympathetic ganglia due to both its pressor effects and to direct stimulation of ETB receptors. Thus O2 in sympathetic ganglia may participate in ET-dependent hypertension by facilitating nicotinic neurotransmission. 20-Hydroxyeicosatetraenoic acid (HETE) synthesis may mediate cerebral vasoconstriction after subarachnoid hemorrhage (SAH), although the factors released by clotting blood that release 20-HETE and the mechanisms by which 20-HETE interacts with the other constricting factors to reduce cerebral