MP25-02 DIVERGENT RESPONSES OF MICE LACKING TAMM-HORSFALL PROTEIN, OSTEOPONTIN OR BOTH TO HYDROXYPROLINE-INDUCED HYPEROXALURIA

Abstract

You have accessJournal of UrologyStone Disease: Basic Research II1 Apr 2014MP25-02 DIVERGENT RESPONSES OF MICE LACKING TAMM-HORSFALL PROTEIN, OSTEOPONTIN OR BOTH TO HYDROXYPROLINE-INDUCED HYPEROXALURIA Feng He, Yan Liu, John Lieske, Herbert Lepor, and Xue-Ru Wu Feng HeFeng He More articles by this author , Yan LiuYan Liu More articles by this author , John LieskeJohn Lieske More articles by this author , Herbert LeporHerbert Lepor More articles by this author , and Xue-Ru WuXue-Ru Wu More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.304AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although mice lacking Tamm-Horsfall protein (THP) or osteopontin (OPN) are prone to spontaneous intra-renal calcification, their responses to experimental hyperoxaluria, particularly to agents that presumably induce minimal renal injury remain to be determined. This study analyzes the effects of THP and OPN deficiency, singly or in a combination, to overload of hydroxy-L-proline (HLP) – a precursor of oxalate, in order to shed light on how urinary macromolecules interface with oxalate supersaturation in nephrolithiasis. METHODS Wild-type, THP knockout (KO), OPN KO and THP/OPN double KO mice (all 2-3 months old) were treated with 5% HLP in drinking water for 1- or 4-weeks. 24-hour urine samples were collected at the end of treatment and concentrations of calcium, oxalate and other electrolytes were determined. Intra-renal crystallization was detected by von Kossa staining and transmission electron microscopy (TEM). Expression of OPN and THP was studied using Real-time PCR, Western blotting and antibody staining. Renal injury of HLP-treated mice was compared with ethylene glycol-treated mice. RESULTS Urine concentrations of oxalate doubled at 1 week and quadrupled at 4 weeks over un-treated mice, but they did not differ significantly between wild-type, THP KO, OPN KO and THP/OPN mice. However, intra-renal calcification varied dramatically at 4 weeks, with wild-type mice devoid of any crystal, OPN KO developing a small number of crystals primarily in the papillae, THP KO developing a moderate number of crystals throughout the nephron, and THP/OPN KO developing a large number of crystals throughout the nephron and papillae. Crystals were primarily intra-tubular and adhered to the luminal membrane in all KO mice. THP/OPN KO mice formed large plugging crystals inside the ducts of Bellini and renal pelvis. TEM showed loosely packed crystals with interspersed electron-dense and -loose rings. Without THP, HLP induced much greater amounts of OPN than with THP. In contrast, HLP did not induce THP in the absence of OPN. Finally, HLP elicited much lower amounts of apoptotic signals such as caspase 3, lipocalin and DNA fragmentation than ethylene glycol. CONCLUSIONS These results indicate that deficiency of urinary macromolecules such as THP and OPN increases the risk of intra-renal calcinosis under hyperoxaluria and that THP is a constitutive inhibitor and OPN is an inducible inhibitor of renal calcification. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e267 Peer Review Report Advertisement Copyright & Permissions© 2014MetricsAuthor Information Feng He More articles by this author Yan Liu More articles by this author John Lieske More articles by this author Herbert Lepor More articles by this author Xue-Ru Wu More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...