Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney

Xiaoxin X. Wang, Komuraiah Myakala, Andrew E. Libby, Ewa Krawczyk, Julia Panov, Bryce A. Jones, Kanchan Bhasin, Nataliia Shults, Yue Qi, Kristopher W. Krausz, Patricia M. Zerfas, Shogo Takahashi, Parnaz Daneshpajouhnejad, Avi Titievsky, Elizaveta Taranenko, Cyrielle Billon, Arindam Chatterjee, Bahaa Elgendy, John K. Walker, Chris AlbaneseJeffrey B. Kopp, Avi Z. Rosenberg, Frank J. Gonzalez, Udayan Guha, Leonid Brodsky, Thomas P. Burris, Moshe Levi

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)1969-1987
Number of pages19
JournalAmerican Journal of Pathology
Volume193
Issue number12
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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