Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice

• Published in: Scientific reports 2020-01, Vol.10 (1), p.87, Article 87
• Main Authors: Almeida, Youri E., Fessel, Melissa R., do Carmo, Luciana Simão, Jorgetti, Vanda, Farias-Silva, Elisângela, Pescatore, Luciana Alves, Gamarra, Lionel F., Andrade, Maria Claudina, Simplicio-Filho, Antonio, Mangueira, Cristóvão Luis Pitangueiras, Rangel, Érika B., Liberman, Marcel
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 14/63; 64/60; 692/699/1585/104/1586; 692/699/2743/137/138; 692/699/2743/137/773; 692/699/2743/393; 692/699/75/593/2193; 82/80; 96/34; Animal models; Animals; Arteries; Bone diseases; Bone morphogenetic protein 2; Bone morphogenetic proteins; Calcification; Calcification (ectopic); Calcium; Calcium (blood); Calcium-Regulating Hormones and Agents - pharmacology; Cholecalciferol - pharmacology; Creatinine; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 2 - physiopathology; Dietary Supplements; End-stage renal disease; Humanities and Social Sciences; Insulin; Insulin Resistance; Kidney diseases; Kidney Diseases - etiology; Kidney Diseases - pathology; Kidneys; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mineralization; multidisciplinary; Obesity; Obesity - physiopathology; Renal function; Science; Science (multidisciplinary); Supplements; Urine; Vascular Calcification - complications; Vitamin D3
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-55501-3

Diabetes mellitus accelerates vascular calcification (VC) and increases the risk of end-stage renal disease (ESRD). Nevertheless, the impact of VC in renal disease progression in type 2 diabetes mellitus (T2DM) is poorly understood. We addressed the effect of VC and mechanisms involved in renal dysfunction in a murine model of insulin resistance and obesity (ob/ob) , comparing with their healthy littermates (C57BL/6). We analyzed VC and renal function in both mouse strains after challenging them with Vitamin D 3 (VitD 3 ). Although VitD 3 similarly increased serum calcium and induced bone disease in both strains, 24-hour urine volume and creatinine pronouncedly decreased only in ob/ob mice. Moreover, ob/ob increased urinary albumin/creatinine ratio (ACR), indicating kidney dysfunction. In parallel, ob/ob developed extensive intrarenal VC after VitD 3 . Coincidently with increased intrarenal vascular mineralization, our results demonstrated that Bone Morphogenetic Protein-2 (BMP-2) was highly expressed in these arteries exclusively in ob/ob . These data depict a greater susceptibility of ob/ob mice to develop renal disease after VitD 3 in comparison to paired C57BL/6. In conclusion, this study unfolds novel mechanisms of progressive renal dysfunction in diabetes mellitus (DM) after VitD 3 in vivo associated with increased intrarenal VC and highlights possible harmful effects of long-term supplementation of VitD 3 in this population.