Perspectives in Pharmacology Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Hydrogen sulfide (H2S) is enzymatically generated in mammalian tissues from either L-cysteine or L-homocysteine. H2S possesses multiple biological activities, including regulation of vascular tone and blood pressure. Hydrogen sulfide produced in endothelial cells, vascular smooth muscle cells, and perivascular adipose tissue dilates blood vessels by activating ATP-sensitive potassium channels. In addition, H2S produced locally within the kidney stimulates natriuresis and diuresis by increasing glomerular filtration and inhibiting tubular sodium reabsorption. Because H2S is oxidized in mitochondria in pO2-dependent manner and ambient pO2 is physiologically low in the renal medulla, it is expected that the activity of H2S is higher in the medullary region than the cortical region. H2S, accumulating in increased amounts in the renal medulla under hypoxic conditions, may function as an oxygen sensor that restores O2 balance by increasing medullary blood flow, reducing energy requirements for tubular transport, and directly inhibiting mitochondrial respiration. Hypoxia is an important pathogenic factor in many renal diseases, such as ischemia/reperfusionor nephrotoxin-induced acute renal failure, progression of chronic nephropathies, diabetic nephropathy, and arterial hypertension. Deficiency of endogenous H2S may contribute to the pathogenesis of these pathologies by compromising medullary oxygenation, and administration of H2S donors may be of therapeutic value in these disorders. Studies performed during the last decade indicate that, apart from NO and CO, H2S is the third “gasotransmitter” involved in the regulation of various physiological functions, including vascular tone and blood pressure, inflammatory reaction, neurotransmission and gastrointestinal system function. H2S is enzymatically synthesized in three metabolic pathways (Fig. 1): 1) desulfhydration of L-cysteine or L-homocysteine by cystathionine -lyase (CSE, EC 4.4.1.1), 2) desulfhydration of L-cysteine by cystathionine -synthase (CBS, EC 4.2.1.22), and 3) transamination of L-cysteine by cysteine aminotransferase (identical with aspartate aminotransferase) to 3-mercaptopyruvate, followed by its desulfhydration to pyruvate by 3-mercaptopyruvate sulfurtransferase (3-MST, EC 2.8.1.2). Hydrogen sulfide activates ATP-sensitive potassium channels (KATP) in various cells, although many other signaling mechanisms have also been described. H2S is inactivated by binding to hemoglobin to form sulfhemoglobin, excretion in exhaled air, and, first and foremost, oxidation in mitochondria. Many studies addressed the role of H2S in the regulation of vascular tone and blood pressure. Indeed, it is suggested that H2S deficiency may contribute to the pathogenesis of arterial hypertension both in experimental animal models and in humans. Recently, renal synthesis and activity of H2S have been characterized (Xia et al., 2009). Because renal sodium handling has a prominent role in the long-term regulation of blood pressure (apart from vascular tone), renal effects of this gas are of great interest for the cardiovascular pharmacologist. In addition, it is well established that renal medulla is a hypoxic environment and that H2S metabolism is O2-dependent. The possible relationship between renal hypoxia and H2S signaling in physiologic and pathologic conditions is addressed in this article. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.110.166637. ABBREVIATIONS: CSE, cystathionine -lyase; CBS, cystathionine -synthase; 3-MST, 3-mercaptopyruvate sulfurtransferase; CO, carbon monoxide; COX-2, cyclooxygenase-2; GFR, glomerular filtration rate; HIF-1, hypoxia-induced factor; HO-1, heme oxygenase-1; H2S, hydrogen sulfide; KATP, ATP-sensitive potassium channels; mTAL, medullary thick ascending limb; NCC, sodium/chloride cotransporter; NKCC, sodium/potassium/chloride cotransporter; NO, nitric oxide; SQR, sulfide/quinone oxidoreductase; GYY4137, morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate. 0022-3565/10/3342-358–363$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 334, No. 2 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 166637/3602607 JPET 334:358–363, 2010 Printed in U.S.A. 358 at A PE T Jornals on Sptem er 3, 2017 jpet.asjournals.org D ow nladed from Role of H2S in the Regulation of Vascular Tone and Blood Pressure Initially, it was suggested that, in the blood vessels, H2S is produced exclusively by CSE expressed in vascular smooth muscle cells and activates KATP channels in these cells, leading to membrane hyperpolarization, reduced voltagedependent Ca influx, and, ultimately, vasorelaxation (Zhao et al., 2001). However, more recent studies indicate that the situation is more complex. H2S is synthesized also by endothelial cells, at least in rodents. In mice aortic endothelial cells, H2S is synthesized by CSE, and its production is stimulated by cholinergic agonists (Yang et al., 2008). Thus, H2S is suggested to be one of the endotheliumdependent relaxing factors. CSE is not expressed in rat endothelial cells; however, H2S is synthesized in these cells in a 3-MST-dependent manner (Shibuya et al., 2009). H2S is also produced by perivascular adipose tissue (Fang et al., 2009). Moreover, H2S, especially at low concentrations, may trigger some vasoconstrictor mechanisms, such as direct inhibition of endothelial NO synthase or inactivation of NO by binding it to form inactive nitrosothiol (Ali et al., 2006). Nevertheless, arterial hypertension is observed in CSE knockout mice, indicating that the net effect of endogenous H2S is definitely antihypertensive (Yang et al., 2008). Plasma H2S concentration as well as vascular CSE expression and activity are lower in experimental models of hypertension, such as spontaneously hypertensive rat, and hypertension induced by NO synthase inhibitors (Wagner, 2009). On the other hand, chronic administration of CSE inhibitor propargylglycine, increases blood pressure in normotensive animals (Yan et al., 2004). Recently, it has been demonstrated that plasma H2S is lower in 25 children with essential hypertension compared with 66 normotensive controls (Chen et al., 2007). Taken together, these data indicate that H2S is involved in the regulation of blood pressure and that its deficiency may contribute to hypertension.