Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney.
This mouse study investigated the role of estrogen-related receptors (ERRs) in age-related kidney decline, focusing on mitochondrial dysfunction and inflammation as key mechanisms. The researchers first observed that ERR expression was reduced in both aging human and mouse kidneys, and that lifelong caloric restriction (CR) preserved ERR levels in mice. They then treated 21-month-old mice (equivalent to elderly) for 8 weeks with a pan-ERR agonist (SLU-PP-332) or for 3 weeks with a STING pathway inhibitor (C-176). The ERR agonist treatment reversed age-associated increases in albuminuria (a marker of kidney damage), podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, acting through the cGAS-STING and STAT3 signaling pathways — effects resembling those of caloric restriction. STING inhibition reduced inflammatory cytokines and the senescence marker p21, but also unexpectedly restored mitochondrial pathway components (PGC-1α, ERRα, mitochondrial complexes, MCAD). The study identifies ERRs as potential CR mimetics and highlights the cGAS-STING pathway as a link between mitochondrial dysfunction and renal inflammation in aging. Key limitations include reliance on animal models, short treatment durations, and the absence of human interventional data.
Why this grade: All interventional experiments were conducted exclusively in aged mice, with human kidney data limited to observational expression analysis; no human clinical trial or controlled intervention was performed.
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. This study examined the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation. The ERRs were decreased in both aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). A pan-ERR agonist, SLU-PP-332, was used to treat 21-month-old mice for 8 weeks. In addition, 21-month-old mice were treated with a stimulator of interferon genes (STING) inhibitor, C-176, for 3 weeks. Remarkably, similar to CR, an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, via the cyclic GMP-AMP synthase-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/cyclin dependent kinase inhibitor 1A (Cdkn1a), but also unexpectedly reversed the age-related decreases in PPARG coactivator (PGC)-1α, ERRα, mitochondrial complexes, and medium chain acyl coenzyme A dehydrogenase (MCAD) expression. These studies identified ERRs as CR mimetics and as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.
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