Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Abstract

logical evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na ϩ reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.superoxide (O 2 ·Ϫ ); hydrogen peroxide (H2O2); nitric oxide (NO); NAD(P)H oxidase; mTAL; medullary blood flow; kidney; Dahl SS rats REACTIVE OXYGEN SPECIES (ROS) are chemically reactive molecules derived from oxygen, whose role as mediators of intracellular signaling cascades is well recognized. The following is a brief review of physiological data linking superoxide (O 2 ·Ϫ ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO) production in the medullary thick ascending limbs of Henle (mTAL) to sodium (Na ϩ ) homeostasis, the regulation of medullary blood flow (MBF), and the long-term regulation of arterial blood pressure. MBF to the renal medulla can be importantly controlled by the constriction and dilation of the descending vasa recta (VR) capillaries, which branch from the efferent arterioles of the juxtamedullary glomeruli (49, 147, 149) and whose tone is controlled by the smooth muscle-like pericytes (49, 90, 146 -149). The role of NO cross talk from mTAL to surrounding VR in the renal medulla has been reviewed in detail elsewhere (19, 33) and will be discussed here largely with regard to its ROS-related counterregulatory functions. The present review will first summarize data showing that either the excess endogenous production or reduced scavenging of O 2 ·Ϫ or H 2 O 2 within the renal medulla results in a decrease in MBF and Na ϩ excretion, leading to hypertension and renal injury. Second, evidence will be summarized supporting the hypothesis that a high dietary salt intake results in increased luminal flow and delivery of NaCl to the mTAL, thereby signaling via both mechanical forces (stretch and shear) and increased Na ϩ transport, an increased mitochondrial and membrane NA-D(P)H oxidase production of O 2 ·Ϫ and H 2 O 2 . Third, studies will be reviewed showing that reduction of MBF leads to hypertension a...

Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle?

“…Loss of Hv1 also significantly blunted hypertensive renal injury in high-salt diet-fed Dahl SS rats (39). Although these findings are, in part, consistent with our overriding hypothesis that augmented outermedullary NADPH oxidase activity and consequent oxidative stress lead to renal injury in the Dahl SS rat strain when fed a high-salt diet (14), our data do not support significant involvement of Hv1 in the development of hypertension, and a number of critical questions remain regarding the role of Hv1 in the pathophysiology of the Dahl SS rat model. Systemic loss of Hv1 is much less effective at reducing blood pressure in Dahl SS rats than that reported following deletion of subunits of the NADPH oxidase (19,31).…”

“…O 2 ·Ϫ is an oxygen-radical produced from a variety of endogenous sources (3). As O 2 ·Ϫ can scavenge NO, which is a potent vasodilator of the medullary circulation, elevated medullary O 2 ·Ϫ levels may promote renal medullary ischemia by reducing the bioavailability of NO (14). O 2 ·Ϫ may also have additional biological actions that promote the development of hypertension independent of its actions of renal hemodynamics.…”

“…Much evidence indicates that within the renal medulla, O 2 ·Ϫ acts as a signaling molecule, stimulating a number of transporters involved in renal Na reabsorption either directly or by reducing NO bioavailbilty (67). As such, elevated O 2 ·Ϫ levels are thought to be prohypertensive in that they are likely to promote both renal Na reabsorption and reduced medullary perfusion (14,57).…”

Increased Muscle Mass Protects Against Hypertension and Renal Injury in Obesity

“…Several reports have described a causal role for NOX4 in renal dysfunction that can lead to hypertension 50, 51. In salt‐sensitive rats, urinary hydrogen peroxide has been shown to be elevated with increased renal perfusion pressure, and deletion of renal NOX4 attenuates hypertension 52, 53, 54. In our obese mouse model, NOX4 expression is elevated in renal tissue and urinary hydrogen peroxide is increased in both concentration and daily excretion, whereas expression of other NOX isoforms was unchanged.…”

Proteomic approaches to the study of renal mitochondria

“…Changes in renal mitochondria in rat models of hypertension include alterations in respiratory functions 89 and oxidative stress 90,91 and renal mitochondria represent possible therapeutic target 92 . Protein expression profiles of the kidney in spontaneously hypertensive rats revealed decreased expression of NADPH dependent mitochondrial isocitrate dehydrogenase 93 .…”