Grant: CIHR Fellowship

Chronic Kidney Disease (CKD) is characterized by structural abnormalities and impaired kidney function. Inadequate filtration of wastes and minerals (including phosphate) leads to serious disruption in mineral metabolism and bone disorder (Mineral and Bone Disorder; MBD). In CKD-MBD patients, phosphate retention in blood triggers secretion of a hormone called fibroblast growth factor 23 (FGF23) to promote renal phosphate excretion. However, FGF23 blocks the generation of the active form of vitamin D. As vitamin D is essential in calcium absorption, low vitamin D causes low blood calcium level, stimulating the production of parathyroid hormone (PTH) by parathyroid glands. Elevated PTH levels restore blood calcium by bone breakdown, resulting in bone loss and fractures. Currently, no drugs can improve both vitamin D levels and renal phosphate excretion. Although PTH usually accomplishes these tasks, CKD-MBD patients do not show expected PTH effects on mineral metabolism, despite the high level of PTH. Therefore, we hypothesized that targeting the downstream mediator of PTH signaling pathway would bypass PTH resistance, yet still bring PTH-like effects to help CKD-MBD. Recently, a family of enzymes called salt-inducible kinases (SIKs) was reported to participate in the actions of PTH in bone. To test if SIKs participate in renal PTH actions, we will use cutting-edge genome editing and pharmacologic approaches in multiple cell lines, as well as two mouse models. The role of SIK deletion in kidney will be determined in mice using a genetic engineering technique known as Cre-lox system. Then, the effects of a SIK inhibitor will be studied in CKD mouse models with kidney injury to examine its therapeutic potential. Considering high prevalence of CKD worldwide (about 13.4%), and at least 4 million Canadians suffering from this chronic disease, this study will give insight into a novel approach in managing CKD-MBD and understanding PTH/SIK signaling in kidney.