Tuesday, January 28, 2025
1/28/2025
Chronic kidney disease (CKD) affects almost 15% of Americans, and renal injury often targets the renal tubule epithelia. How these tubules respond can determine whether the kidney undergoes repair or tubulointerstitial fibrosis (TIF), the common hallmark of progressive CKD. This proposal focuses on understanding how chronic renal injury induces changes in the renal tubular cell cycle and metabolism and how these changes affect tubular survival and the development of TIF. It is well known that cell cycle, metabolism, and mitochondrial function are all closely coordinated processes, but it is not clear how epithelial G1 to S cell cycle progression affects metabolism in the CKD kidney. Preliminary data suggests that reducing cell cycle progression from G1 to S phase in renal tubules protects against fibrosis in rodent CKD models and decreases tubular apoptosis. In addition, reducing G1 to S progression increased glucose oxidation, the metabolism of glucose to pyruvate which is then oxidized in the mitochondria through the citric acid cycle and electron transport chain. This proposal will test the hypothesis that reducing epithelial G1 to S phase progression in CKD protects against epithelial injury and fibrosis through altered metabolism. To test this, Aim 1 will use either a pharmacologic (palbociclib) or a genetic (conditionally delete cyclin D1 in renal tubules) approach to reduce G1 to S cell cycle progression in mice. We hypothesize that decreasing G1 progression to S phase in epithelial cells is protective in CKD models by reducing tubular injury and fibrosis. Our preliminary data show that reducing cell cycle progression in both injured kidney tissue and in isolated tubule cells also suppresses signaling pathways and inflammatory cytokines associated with kidney injury. This aim investigates how reducing cell cycle progression may alter these signaling pathways to reduce tubule injury and myofibroblast activation by autocrine and paracrine signaling, respectively. The second aim investigates the metabolic changes that occur in injured tubules with reduced G1 to S phase progression using the Seahorse bioflux analyzer, 14C-pyruvate oxidation studies ex vivo, and stable isotopic metabolomics. We hypothesize that reducing epithelial cell cycle progression increases glucose oxidation leading to better epithelial survival and less fibrosis, in part, through the AMP-activated protein kinase pathway. We will also investigate how glucose oxidation in renal tubules, independent of metabolism, affects the response to chronic injury. The impact of cell cycle progression on mitochondrial function and structure will also be defined using Oroboros and super- resolution microscopy. These studies should provide novel information about how changes in epithelial cell cycle and metabolism affect the response to chronic renal injury with the potential identification of novel therapeutic targets to treat CKD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).