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Title: Proximal Tubule β2-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury.

Authors: Cameron, Robert B; Gibbs, Whitney S; Miller, Siennah R; Dupre, Tess V; Megyesi, Judit; Beeson, Craig C; Schnellmann, Rick G

Published In J Pharmacol Exp Ther, (2019 04)

Abstract: Acute kidney injury (AKI) is the rapid loss of renal function after an insult, and renal proximal tubule cells (RPTCs) are central to the pathogenesis of AKI. The β2-adrenergic receptor (β2AR) agonist formoterol accelerates the recovery of renal function in mice after ischemia-reperfusion injury (IRI) with associated rescue of mitochondrial proteins; however, the cell type responsible for this recovery remains unknown. The role of RPTCs in formoterol-induced recovery of renal function was assessed in a proximal tubule-specific knockout of the β2AR (γGT-Cre:ADRB2Flox/Flox). These mice and wild-type controls (ADRB2Flox/Flox) were subjected to renal IRI, followed by once-daily dosing of formoterol beginning 24 hours post-IRI and euthanized at 144 hours. Compared with ADRB2Flox/Flox mice, γGT-Cre:ADRB2Flox/Flox mice had decreased renal cortical mRNA expression of the β2AR. After IRI, formoterol treatment restored renal function in ADRB2Flox/Flox but not γGT-Cre:ADRB2Flox/Flox mice as measured by serum creatinine, histopathology, and expression of kidney injury marker-1 (KIM-1). Formoterol-treated ADRB2Flox/Flox mice exhibited recovery of mitochondrial proteins and DNA copy number, whereas γGT-Cre:ADRB2Flox/Flox mice treated with formoterol did not. Analysis of mitochondrial morphology by transmission electron microscopy demonstrated that formoterol increased mitochondrial number and density in ADRB2Flox/Flox mice but not in γGT-Cre:ADRB2Flox/Flox mice. These data demonstrate that proximal tubule β2AR regulates renal mitochondrial homeostasis. Formoterol accelerates the recovery of renal function after AKI by activating proximal tubule β2AR to induce mitochondrial biogenesis and demonstrates the overall requirement of RPTCs in renal recovery.

PubMed ID: 30709866 Exiting the NIEHS site

MeSH Terms: Animals; Formoterol Fumarate/pharmacology*; Kidney Tubules, Proximal/drug effects*; Kidney Tubules, Proximal/metabolism; Kidney Tubules, Proximal/pathology; Kidney Tubules, Proximal/physiopathology*; Male; Mice; Mitochondria/drug effects*; Mitochondria/pathology; Receptors, Adrenergic, beta-2/metabolism*; Recovery of Function/drug effects; Reperfusion Injury/metabolism; Reperfusion Injury/pathology*; Reperfusion Injury/physiopathology*; Signal Transduction/drug effects

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