RT Journal Article
SR Electronic
T1 ERR agonism reverses mitochondrial dysfunction and inflammation in the aging kidney
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 755801
DO 10.1101/755801
A1 Xiaoxin X. Wang
A1 Shogo Takahashi
A1 Andrew E. Libby
A1 Komuraiah Myakala
A1 Bryce A. Jones
A1 Kanchan Bhasin
A1 Yue Qi
A1 Kristopher Krausz
A1 Patricia Zerfas
A1 Julia Panov
A1 Thomas J. Velenosi
A1 Daxesh P. Patel
A1 Parnaz Daneshpajouhnejad
A1 Brandon Ginley
A1 Pinaki Sarder
A1 Avi Titievsky
A1 Vadim Sharov
A1 Boris Ostretsov
A1 Jeffrey B Kopp
A1 Avi Z Rosenberg
A1 Frank J Gonzalez
A1 Udayan Guha
A1 Leonid Brodsky
A1 Thomas Burris
A1 Moshe Levi
YR 2019
UL http://biorxiv.org/content/early/2019/09/05/755801.abstract
AB 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, endoplasmic reticulum stress, oxidative stress, inflammation, altered lipid metabolism, and profibrotic growth factors in the kidney, which collectively contribute to age-related kidney disease. With increasing population of older individuals and the increasing incidence of acute kidney injury and chronic kidney disease, identifying preventable or treatable aspects of age-related nephropathy becomes of critical importance. In this regard we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs), whose expression levels are decreased in aging human and mouse kidneys. Our studies have identified the estrogen related receptors ERRα, ERRβ, and ERRγ as important modulators of age-related mitochondrial dysfunction, cellular senescence, and inflammation. Significantly these pathways are also regulated by lifelong caloric restriction (CR), which is known to prevent several age-related complications including kidney disease. ERRα, ERRβ, and ERRγ expression levels are decreased in the aging kidney, and CR and pharmacological treatment with a pan ERR agonist results in increases in expression of ERRα, ERRβ, and ERRγ in the kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related mitochondrial dysfunction, the cellular senescence marker p21, and inflammatory cytokines, including the STAT3 and STING signaling pathways.