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. Vascular calcification (VC) is a pathological condition which causes loss of arterial elasticity and augments vascular stiffening associated with increased cardiac work 1,2. This contributes to several cardiovascular diseases such as systemic arterial hypertension, coronary artery and cerebrovascular disease, congestive heart failure, and end-stage renal disease (ESRD) 3. Previously thought as a process of physiological aging, VC is currently known as an active and complex process, characterized by increased calcifying signaling agonists that overcome inhibitory mediators and resembles skeleton ossification 1,2. Diabetes mellitus is a huge public health problem in the world. It is estimated that diabetic population will reach 430 million people in 2030. Incidence of ESRD is up to 10 times as high in adults with diabetes as those without 4. ESRD attributable to diabetes is 12-55% 4. In the last decades, numerous advances have been incorporated to the treatment of ESRD. However, the incidence of renal replacement therapy and mortality rates in this population remains high 5,6. Epidemiological studies describe ESRD and VC as independent cardiovascular risk factors 5. However, ESRD patients are usually identified with VC 7,8 , and ESRD together with diabetes mellitus accelerates VC progression 7-9 .