Abstract
Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.
Highlights
The role of salt wasting and volume depletion in the pathogenesis of hypercalciuria and hyperphosphateuria is poorly understood
Serum calcium and phosphate levels were reduced by approximately 22% and 10%, respectively, in pendrin/NCC-dKO mice compared to WT mice (Fig 1A & 1B)
Our studies indicate that simultaneous deletion of pendrin and NCC genes gives rise to animals with phenotypic anomalies that are disproportionate to the physiological function of these molecules [9]
Summary
The role of salt wasting and volume depletion in the pathogenesis of hypercalciuria and hyperphosphateuria is poorly understood. Age associated derangements in renal ion transport machinery is well documented, and is important in salt wasting and volume depletion in the elderly [1, 2]. A monogenic disorder associated with primary salt wasting, volume depletion, and hypercalciuria is Bartter’s Syndrome [3]. Neonatal Bartter’s Syndrome is used synonymously with Hyperprostaglandin E syndrome (HPS) and is characterized by enhanced renal and systemic generation of prostaglandin E2 (PGE-2), which is thought to be largely responsible for the aggravation of its associated clinical symptoms [6,7,8]. Hypercalciuria, impaired urinary concentrating ability in the face of volume depletion, metabolic alkalosis and the activation of the renin angiotensin system are the most salient features of neonatal Bartter’s Syndrome/HPS [6, 8]
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