Role of Estrogen Related Receptors in Age Related Kidney Disease

Life-long caloric restriction (CR) prevents age-related decline in kidney health, including impaired mitochondrial function, lipid accumulation, and inflammation. We determined that renal expression of the nuclear hormone receptors the estrogen related receptors (ERRs) ERRα, ERRβ, and ERRγ decreases with age, and that CR prevents this decrease. We found that treatment of 22-month-old mice with a pan ERR agonist upregulates the renal expression of ERRα and ERRγ, and reverses the increase in urinary albumin excretion, the impaired mitochondrial function, and the increase in inflammation. However, knowledge gaps remain, including 1) the podocyte and tubule specific effects of ERRα or ERRγ, and if beneficial effects of ERRs on age-related kidney disease depend on 2) alterations in kidney lipid composition and 3) proinflammatory immune cells. Hypothesis: We hypothesize that ERRs play an important role in modulating age-related kidney disease. We propose that: (1) decreased expression of ERRα or ERRγ accelerates age-related kidney diseases, whereas increased expression of ERRα or ERRγ slows age-related kidney disease (SA1); (2) ERRs modulate age-related kidney disease by inhibiting the increased synthesis and accumulation of ceramides and glycosphingolipids (SA2); (3) ERRs modulate age-related kidney disease by inhibiting proinflammatory immune cells (SA3). In SPECIFIC AIM 1, we will test the hypothesis that inducible decreased expression of ERRα or ERRγ in the podocytes or the tubules accelerates, whereas inducible increased expression of ERRα or ERRγ in the podocytes or tubules slows age-related kidney disease. In SPECIFIC AIM 2, we will test the hypothesis that ERRs modulate age-related kidney disease by inhibiting the increased synthesis and accumulation of ceramides and glycosphingolipids. In SPECIFIC AIM 3, we will test the hypothesis that ERRs modulate age-related kidney disease by inhibiting inflammatory immune cells.