title: Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.
abstract: Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.
authors.affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.|Dept. of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wilco P
authors.initials: WP
authors.lastname: Pulskens
authors.affiliation: Dept. of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: Verkaik
authors.affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Fareeba
authors.initials: F
authors.lastname: Sheedfar
authors.affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ellen P
authors.initials: EP
authors.lastname: van Loon
authors.affiliation: Dept. of Pediatrics, Molecular Genetics Section, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: Dept. of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Vervloet
authors.affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost G
authors.initials: JG
authors.lastname: Hoenderop
authors.affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D004573:Electrolytes / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D000090265:Klotho Proteins; D008297:Male; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000378:metabolism*; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology*; D015398:Signal Transduction; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism
chemical_list: D004573:Electrolytes; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium