Half of diabetic patients ultimately develop diabetic kidney disease (DKD), which is the leading cause of chronic kidney disease (CKD). In CKD patients, heart failure is highly prevalent and strongly associated with mortality. Elevated plasma phosphate levels (hyperphosphatemia) are common in CKD and are a serious risk factor in the progression of cardiovascular disease (CVD) and vascular calcification (VC). Of note, an increase in fibroblast growth factor 23 has been shown to reduce plasma phosphate in the early stages of CKD at the expense of developing left ventricular hypertrophy. Due to the kidney’s ability to increase phosphate excretion in response to elevated parathyroid hormone levels, hyperphosphatemia only develops in later stages of CKD. In the proximal tubule of the kidney, the sodium/phosphate cotransporter 2a (Npt2a) plays an important role in reabsorbing 70% of the filtered phosphate. Currently, treatment of hyperphosphatemia is limited to dietary phosphate restriction, phosphate binders and nicotinamide, which unfortunately often are ineffective. We recently described a new approach to manage hyperphosphatemia by inhibiting Npt2a with a newly developed Npt2a inhibitor (Npt2a-I, PF-06869206). We observed a significant reduction in plasma phosphate levels as well as parathyroid hormone levels in normal and CKD mice after an acute treatment with Npt2a-I. Therefore, we hypothesize that chronic treatment of Npt2a-I in DKD mice will decrease the progression of hyperphosphatemia associated complications. Our specific aims will study the therapeutic effect of Npt2a-I in the progression of hyperphosphatemia associated CVD and VC. Studies will be carried out in db/db or db/db uninephrectomized (Nx) or db/db Npt2a-/- Nx mice. The latter will serve as a proof-of-concept experiment. This study will investigate a new therapeutic approach towards hyperphosphatemia and its associated progression of CVD and VC in the context of diabetes. These experiments will be instrumental to determine if Npt2a inhibition is a valuable therapeutic intervention for diabetic complications.