title: A murine model of phosphate nephropathy.
abstract: We established a murine model of phosphate nephropathy with secondary hyperparathyroidism. db/db mice, which develop obesity and type 2 diabetes mellitus, were uninephrectomized at the age of 6 weeks and were fed either standard chow or a phosphorus-rich diet during the next 8 weeks. Thereafter, renal cryosections showed abundant tubular casts with a strong histochemical von Kossa reaction in all db/db mice on the phosphorus-rich diet but none in the controls. X-ray diffraction and Raman spectroscopy proved that these tubular casts consist mostly of hydroxyapatite Ca₅(PO₄)₃(OH). These intraluminal precipitations were located in distal tubuli and collecting ducts and were associated with degenerative tubular changes and peritubular infiltration of T cells and macrophages. In line, kidneys of db/db mice on the phosphorus-rich diet displayed significantly increased mRNA expression of the T(H)1 cytokines interferon γ, IL-6, and tumor necrosis factor α. In addition, mice developed signs of secondary hyperparathyroidism as shown by elevated serum phosphate, decreased serum calcium, and increased parathyroid hormone, osteopontin, and fibroblast growth factor 23 levels. db/db mice on the phosphorus-rich diet also presented with significantly lower body weight, lower homeostasis model assessment of insulin resistance index, and hypertrophic cardiomyopathy. Thus, we provide a murine model of phosphate nephropathy and secondary hyperparathyroidism, which can be used for future pharmacologic and pathophysiologic studies to analyze the effect of hyperphosphatemia on renal, metabolic, and cardiovascular phenotypes.
authors.affiliation: Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria. philipp.eller@i-med.ac.at
authors.forename: Philipp
authors.initials: P
authors.lastname: Eller
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Kirsch
authors.forename: Josef J
authors.initials: JJ
authors.lastname: Patsch
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wolf
authors.forename: Andrea
authors.initials: A
authors.lastname: Tagwerker
authors.forename: Ursula
authors.initials: U
authors.lastname: Stanzl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kaindl
authors.forename: Volker
authors.initials: V
authors.lastname: Kahlenberg
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.forename: Josef R
authors.initials: JR
authors.lastname: Patsch
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Rosenkranz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006962:Hyperparathyroidism, Secondary / Q000473:pathology / Q000503:physiopathology; D054559:Hyperphosphatemia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010710:Phosphates / Q000009:adverse effects*; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010710:Phosphates; D054411:Receptors, Leptin