Neal X Chen1, Kalisha O'Neill2, Nader Kassis Akl2, Sharon M Moe3. 1. Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: xuechen@iupui.edu. 2. Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA. 3. Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush VA Medical Center, Indianapolis, IN, USA.
Abstract
BACKGROUND: Calcification can occur in fat in multiple clinical conditions including in the dermis, breasts and in the abdomen in calciphylaxis. All of these are more common in patients with advanced kidney disease. Clinically, hyperphosphatemia and obesity are risk factors. Thus we tested the hypothesis that adipocytes can calcify in the presence of elevated phosphorus and/or that adipocytes exposed to phosphorus can induce vascular smooth muscle cell (VSMC) calcification. METHODS: 3T3-L1 preadipocytes were induced into mature adipocytes and then treated with media containing high phosphorus. Calcification was assessed biochemically and PCR performed to determine the expression of genes for osteoblast and adipocyte differentiation. Adipocytes were also co-cultured with bovine VSMC to determine paracrine effects, and the efficacy of sodium thiosulfate was determined. RESULTS: The results demonstrated that high phosphorus induced the calcification of differentiated adipocytes with increased expression of osteopontin, the osteoblast transcription factor Runx2 and decreased expression of adipocyte transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (CEBPα), indicating that high phosphorus led to a phenotypic switch of adipocytes to an osteoblast like phenotype. Sodium thiosulfate, dose dependently decreased adipocyte calcification and inhibited adipocyte induced increase of VSMC calcification. Co-culture studies demonstrated that adipocytes facilitated VSMC calcification partially mediated by changes of secretion of leptin and vascular endothelial growth factor (VEGF) from adipocytes. CONCLUSION: High phosphorus induced calcification of mature adipocytes, and adipocytes exposed to elevated phosphorus can induce calcification of VSMC in a paracrine manner. Sodium thiosulfate inhibited this calcification and decreased the secretin of leptin and VEGF from adipocytes. These results suggest that adipocyte exposure to elevated phosphorus may be a pathogenic factor in calcification observed in the skin in calciphylaxis and other diseases.
BACKGROUND:Calcification can occur in fat in multiple clinical conditions including in the dermis, breasts and in the abdomen in calciphylaxis. All of these are more common in patients with advanced kidney disease. Clinically, hyperphosphatemia and obesity are risk factors. Thus we tested the hypothesis that adipocytes can calcify in the presence of elevated phosphorus and/or that adipocytes exposed to phosphorus can induce vascular smooth muscle cell (VSMC) calcification. METHODS: 3T3-L1 preadipocytes were induced into mature adipocytes and then treated with media containing high phosphorus. Calcification was assessed biochemically and PCR performed to determine the expression of genes for osteoblast and adipocyte differentiation. Adipocytes were also co-cultured with bovineVSMC to determine paracrine effects, and the efficacy of sodium thiosulfate was determined. RESULTS: The results demonstrated that high phosphorus induced the calcification of differentiated adipocytes with increased expression of osteopontin, the osteoblast transcription factor Runx2 and decreased expression of adipocyte transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (CEBPα), indicating that high phosphorus led to a phenotypic switch of adipocytes to an osteoblast like phenotype. Sodium thiosulfate, dose dependently decreased adipocyte calcification and inhibited adipocyte induced increase of VSMC calcification. Co-culture studies demonstrated that adipocytes facilitated VSMCcalcification partially mediated by changes of secretion of leptin and vascular endothelial growth factor (VEGF) from adipocytes. CONCLUSION: High phosphorus induced calcification of mature adipocytes, and adipocytes exposed to elevated phosphorus can induce calcification of VSMC in a paracrine manner. Sodium thiosulfate inhibited this calcification and decreased the secretin of leptin and VEGF from adipocytes. These results suggest that adipocyte exposure to elevated phosphorus may be a pathogenic factor in calcification observed in the skin in calciphylaxis and other diseases.
Authors: Sagar U Nigwekar; Sophia Zhao; Julia Wenger; Jeffrey L Hymes; Franklin W Maddux; Ravi I Thadhani; Kevin E Chan Journal: J Am Soc Nephrol Date: 2016-04-14 Impact factor: 10.121
Authors: Sagar U Nigwekar; Daniela Kroshinsky; Rosalynn M Nazarian; Jeremy Goverman; Rajeev Malhotra; Vicki Ann Jackson; Mihir M Kamdar; David J R Steele; Ravi I Thadhani Journal: Am J Kidney Dis Date: 2015-05-07 Impact factor: 8.860
Authors: Keith G Avin; Meghan C Hughes; Neal X Chen; Shruthi Srinivasan; Kalisha D O'Neill; Andrew P Evan; Robert L Bacallao; Michael L Schulte; Ranjani N Moorthi; Debora L Gisch; Christopher G R Perry; Sharon M Moe; Thomas M O'Connell Journal: Sci Rep Date: 2021-05-07 Impact factor: 4.379