title: Prostaglandin-E2 Mediated Increase in Calcium and Phosphate Excretion in a Mouse Model of Distal Nephron Salt Wasting.
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.
authors.affiliation: Center on Genetics of Transport, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Departments of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Research Services, Veterans Affairs Medical Center, Cincinnati, OH, United States of America.
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: Center on Genetics of Transport, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Departments of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Research Services, Veterans Affairs Medical Center, Cincinnati, OH, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Barone
authors.affiliation: Center on Genetics of Transport, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Departments of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Cell Biophysics and, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Saeed
authors.initials: S
authors.lastname: Alshahrani
authors.affiliation: Center on Genetics of Transport, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Departments of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Departments of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Smith
authors.affiliation: Center on Genetics of Transport, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Departments of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.|Research Services, Veterans Affairs Medical Center, Cincinnati, OH, United States of America.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Zahedi
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency; D002118:Calcium / Q000378:metabolism*; D004032:Diet; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D053565:Hypercalciuria / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007015:Hypophosphatemia, Familial / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010710:Phosphates / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1 / Q000172:deficiency; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; D010710:Phosphates; C494849:Slc26a4 protein, mouse; D064466:Solute Carrier Family 12, Member 1; D000076988:Sulfate Transporters; D015232:Dinoprostone; D002118:Calcium