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ERR agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

ABSTRACT: A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction, and inflammation, which collectively contribute to age-related kidney disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs are decreased in aging human and mouse kidneys and preserved in aging mice with lifelong caloric restriction (CR). Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. ERRα, ERRβ, and ERRγ levels are decreased in the aging kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and Mcad expression.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Yue Andy Qi

LAB HEAD: Moshe Levi, MD

PROVIDER: PXD020051 | Pride | 2023-08-02

REPOSITORIES: Pride

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			Action	DRS
	20190624_Moshe_TMT_F1.raw	Raw
	20190624_Moshe_TMT_F10.raw	Raw
	20190624_Moshe_TMT_F11.raw	Raw
	20190624_Moshe_TMT_F12.raw	Raw
	20190624_Moshe_TMT_F13.raw	Raw

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Project description:Background: A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. Methods: ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). Pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. Results: Remarkably, only an 8-week treatment with the pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression. Conclusions: Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

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