Proximal tubule b2-adrenergic receptor mediates formoterol-induced recovery of mitochondrial and renal function after ischemia-reperfusion injury

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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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 b2-adrenergic receptor (b2AR) 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 b2AR (gGT-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, gGT-Cre:ADRB2Flox/Flox mice had decreased renal cortical mRNA expression of the b2AR. After IRI, formoterol treatment restored renal function in ADRB2Flox/Flox but not gGT-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 gGT-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 gGT-Cre:ADRB2Flox/Flox mice. These data demonstrate that proximal tubule b2AR regulates renal mitochondrial homeostasis. Formoterol accelerates the recovery of renal function after AKI by activating proximal tubule b2AR to induce mitochondrial biogenesis and demonstrates the overall requirement of RPTCs in renal recovery.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume369
Issue number1
DOIs
StatePublished - Apr 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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