Hypoxia in the renal medulla: implications for hydrogen sulfide signaling

Abstract

Hydrogen sulfide (H(2)S) is enzymatically generated in mammalian tissues from either L-cysteine or L-homocysteine. H(2)S 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, H(2)S produced locally within the kidney stimulates natriuresis and diuresis by increasing glomerular filtration and inhibiting tubular sodium reabsorption. Because H(2)S is oxidized in mitochondria in pO(2)-dependent manner and ambient pO(2) is physiologically low in the renal medulla, it is expected that the activity of H(2)S is higher in the medullary region than the cortical region. H(2)S, accumulating in increased amounts in the renal medulla under hypoxic conditions, may function as an oxygen sensor that restores O(2) 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/reperfusion- or nephrotoxin-induced acute renal failure, progression of chronic nephropathies, diabetic nephropathy, and arterial hypertension. Deficiency of endogenous H(2)S may contribute to the pathogenesis of these pathologies by compromising medullary oxygenation, and administration of H(2)S donors may be of therapeutic value in these disorders.