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
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.