Friday, September 22, 2023
9/22/2023
The proposed studies will test the hypothesis that mitochondrial dysfunction and increased inflammation mediates age-related kidney disease. We propose that increased expression of estrogen related receptors ERRa and ERR¿ improves mitochondrial function, and decreases cGAS-STING signaling, cellular senescence and inflammation, which reverses age-related kidney disease. In addition, the effects of ERRs on senescence, inflammation, and fibrosis are cGAS-STING dependent. Furthermore, increased expression of ERRa and ERR¿ or inhibition of cGAS-STING signaling prevents acute kidney injury mediated by folic acid, LPS, or ischemia/reperfusion In SPECIFIC AIM 1 we will test the hypothesis that increased renal tubular ERRa or ERR¿ will improve mitochondrial function and inflammation and reverse age-related kidney disease. We will determine: A) the effects of renal tubular ERRa or ERR¿ or simultaneous ERRa/ERR¿ increased expression on kidney mitochondrial function, inflammation and kidney disease; B) if renal tubular increases in ERRs prevents acute kidney injury mediated by a) folic acid, b) LPS, or c) ischemia/reperfusion. The rationale for these studies is that all three models result in decreased ERRa and ERR¿ expression in the kidneys; C) direct effects of increased expression of ERRa, ERR¿, or simultaneous ERRa and ERR¿ in human proximal tubular cells. In SPECIFIC AIM 2 we will test the hypothesis that the effects of ERRa or ERR¿ to reverse inflammation and kidney disease in aging are mediated via a cGAS-STING dependent mechanism. We will determine the roles of A) cGAS: generalized or kidney specific cGAS knockout mice treated with ERR; B) STING: generalized or kidney specific STING knockout mice treated with ERR; C) We will determine if treatment of mice with STING inhibitor prevents acute kidney injury mediated by a) folic acid, b) LPS, or c) ischemia/reperfusion. The rationale for these studies is that all three models result in increased cGAS-STING expression in the kidneys. INNOVATION: 1) These studies will determine if inducible increased expression of ERR-a and ERR-¿ in the renal tubules will improve mitochondrial dysfunction, cGAS-STING mediated inflammation and age-related kidney disease. 2) While the effects of ERRs in regulation of mitochondrial function has been studied, mainly in other target organs, the effects of ERRs in regulation of inflammation is novel and has not been studied in the kidney. To this end we will perform mechanistic studies to determine the role of cGAS-STING in regulating inflammation and the effects of ERR in the kidney.
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