The kidneys play a vital role in mineral homeostasis. In this review, the handling of calcium and the methods currently applied to measuring its intracellular concentration are discussed. The bulk of calcium absorption proceeds in proximal tubules, with smaller fractions recovered by thick ascending limbs, distal convoluted tubules, and connecting tubules. Hormonally regulated transcellular calcium absorption is essentially limited to distal convoluted and connecting tubules. At physiological concentrations, parathyroid hormone, calcitonin, and vitamin D increase net calcium absorption. Calcium absorption by polarized epithelial cells is a two-step process wherein calcium enters the cell across apical plasma membranes and exits across basolateral membranes. Recent electrophysiological and pharmacological experiments demonstrate that apical entry is mediated by calcium channels, which are modestly calcium selective, sensitive to dihydropyridine-type calcium channel blockers, and exhibit a wide range of single-channel conductances. Cellular calcium efflux is mediated by Ca(2+)-ATPase and by Na+/Ca2+ exchange. Ca(2+)-ATPase activity is highest in segments that exhibit significant rates of active calcium absorption. Multiple plasma membrane Ca(2+)-ATPase isoforms have been found in the kidney. Several renal Na+/Ca2+ exchange isoforms have been identified, and their role in effecting calcium efflux is under investigation.

Thiazide diuretics inhibit Na+ and stimulateCa2+ absorption in renal distal convoluted tubules. Experiments were performed on immortalized mouse distal convoluted tubule (MDCIT) cells to determine the mechanism underlying the dissociation of sodium from calcium transport and the stimulation of calcium absorption induced by thiazide diuretics. Control rates of 22Na+ uptake averaged 272±35 nmol min-' mg protein-' and were inhibited 40% by chlorothiazide (CTZ, 10'-M). Control rates of MCl-uptake averaged 340±50 nmol min' mg protein-' and were inhibited 50% by CTZ. CTZ stimulated 4"Ca2" uptake by 45% from resting levels of 2.86±0.26 nmol min' mg protein'. Bumetanide (10 -4 M) had no effect on 22Na +, -6CI -, or 45Ca 2+ uptake. Control levels of intracellular calcium activity ([Ca2+1I) averaged 91±12 nM. CTZ elicited concentration-dependent increases of ICa2+J1 to a maximum of 654±31 nM at 10-4 M. Reduction of extracellular Clor addition of NPPB abolished CTZ-induced hyperpolarization. Direct membrane hyperpolarization increased 45Ca2+ uptake whereas depolarization inhibited 45Ca2+ uptake. CTZ-stimulated 45Ca2+ uptake was inhibited by the Ca2+ channel blocker nifedipine (10-5 M). We conclude that thiazide diuretics block cellular chloride entry mediated by apical membrane NaCl cotransport. Intracellular chloride, which under control conditions is above its equilibrium value, exits the cell through NPPB-sensitive chloride channels. This decrease of intracellular chloride hyperpolarizes MDCT cells and stimulates Ca2+ entry by apical membrane, dihydropyridine-sensitive Ca2+ channels. (J. Clin. Invest. 1992. 90:429-438.) Key

Nephropathy is a major contributor to overall morbidity and mortality in diabetic patients. Early renal changes during diabetes include Na retention and renal hypertrophy. Tumor necrosis factor (TNF) is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy. We tested the hypothesis that TNF contributes to Na retention and renal hypertrophy during diabetes. Rats with streptozotocin-induced diabetes exhibit increased urinary TNF excretion, Na retention, and renal hypertrophy through the first 20 days of diabetes. Administration of a soluble TNF antagonist (TNFR:Fc) to diabetic rats reduces urinary TNF excretion and prevents Na retention and renal hypertrophy. TNF stimulates Na uptake in distal tubule cells isolated from diabetic rats, providing a possible mechanism for TNF-induced Na retention. We conclude that urinary TNF contributes to early diabetic nephropathy and may serve as a valuable diagnostic marker. Furthermore, inhibition of TNF during diabetes may attenuate early pathological changes in diabetic nephropathy.

Extracellular calcium homeostasis involves coordinated calcium absorption by the intestine, calcium resorption from bone, and calcium reabsorption by the kidney. This review addresses the mechanism and regulation of renal calcium transport. Calcium reabsorption occurs throughout the nephron. However, distal tubules are the nephron site at which calcium reabsorption is regulated by parathyroid hormone, calcitonin, and 1 alpha,25-dihydroxyvitamin D3 and where the magnitude of net reabsorption is largely determined. These and related observations underscore the view that distal tubules are highly specialized to permit fine regulation of calcium excretion in response to alterations in extracellular calcium levels. Progress in understanding the mechanism and regulation of calcium transport has emerged from application of single cell fluorescence, patch clamp, and molecular biological approaches. These techniques permit the examination of ion transport at the cellular level and its regulation at subcellular and molecular levels. This editorial review focuses on recent and emerging observations and attempts to integrate them into models of cellular calcium transport.

Various types of catecholamine and peptide hormone receptors have been localized to the renal cortex, with the majority of these binding sites located on the proximal tubule. Both subtypes of alpha-adrenergic receptors, angiotensin II (ANG II), parathyroid hormone (PTH), and dopamine (DA) DA-1 receptors have all demonstrated binding sites on this nephron segment. One- to two-thirds of Na+ transport in the proximal nephron is proposed to be mediated by a Na(+)-H+ exchanger. Each of these hormones has been shown to alter Na(+)-H+ exchange activity. The purpose of this study was to examine the interactions of these various hormones on proximal nephron Na(+)-H+ exchange at both physiological and pharmacological concentrations. Na(+)-H+ exchange activity was determined in isolated rat proximal segments by assessing the uptake of 22Na+ that was suppressible by the Na(+)-H+ exchange inhibitor, ethylisopropylamiloride (EIPA). Time course studies indicated that a 1-min preincubation with the hormones followed by a 1-min exposure to 22Na+ was necessary to achieve a steady-state EIPA-suppressible 22Na+ uptake. Selective alpha-adrenergic agonists produced a maximum stimulation of 22Na+ uptake at approximately 10(-6) M final concentration (less than or equal to 192% above the control level of uptake); ANG II produced a maximum increase at 10(-12) M (an 82% increase above the control level). In contrast, PTH and DA inhibited 22Na+ uptake most effectively at 10(-8) M and 10(-6) M, respectively. When submaximal (10(-9) M) concentrations of alpha-agonists were incubated in combination with ANG II, a synergistic effect was observed only with selective alpha 2-agonists.(ABSTRACT TRUNCATED AT 250 WORDS)