Chronic kidney disease (CKD) has become an endemic health crisis that dramatically increases the risk of cardiovascular disease and stroke. Regardless the initial insult, tubulo-interstitial fibrosis (TIF) is the hallmark of late stage CKD, and transforming growth factor-b (TGF-b) is arguably the most potent growth factor in CKD progression. However, TGF-b’s effect varies depending on microenvironment and targeted cell types. Epithelial TGF-b signaling requires the binding activation of a serine/threonine kinase receptor, the TGF-b type II receptor (TbRII) which subsequently activates the Type I receptor (ALK5) and downstream effectors. Previous studies demonstrated that inhibition of TGF-b signaling in the proximal tubule (PT) aggravates renal fibrosis in chronic injury, suggesting that while excessive TGF-b activity is clearly deleterious, some TGF-b signaling may be necessary for a reparative epithelial response to injury. However, the cellular mechanism underlying this surprising TGF-b’s beneficial effect remains unclear.
Our goal is to determine the subcellular mechanisms whereby TGF-b signaling mediates proximal tubule adaptive response to chronic renal injury.
This project investigates how the impact of TGF-b signaling on mitochondria integrity (structure and functional) affects PT response to CKD. Conditional knockout mice lacking TbRII in the PT (gGT-Cre;Tgfbr2fl/fl) and PT cells are respectively used for in vivo and in vitro studies. Mice are injured using three models of CKD (UUO, Aristolochic acid and uninephectomy/Angiotennsin2) and the effect of TGF-b signaling on mitochondria and CKD progression is assessed using biochemistry, molecular biology and histology techniques.