Proximal Tubule beta(2)-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury

摘要

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 beta(2)-adrenergic receptor ((beta(2)AR) 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 beta(2)AR (gamma GT-Cre:ADRB2 (Flox/Flox)) . These mice and wild-type controls (ADRB2 (Flox/Flox)) were subjected to renal IRI, followed by oncedaily dosing of formoterol beginning 24 hours post-IRI and euthanized at 144 hours. Compared with ADRB2 (Flox/Flox) mice, gamma GT-Cre:ADRB2 (Flox/Flox) mice had decreased renal cortical mRNA expression of the beta(2 )AR. After IRI, formoterol treatment restored renal function in ADRB2 (Flox/Flox )but not gamma GT-Cre: ADRB2 (Flox/Flox) mice as measured by serum creatinine, histopathology, and expression of kidney injury marker-1 (KIM-1). Formoterol-treated ADRB2 (Flox/Flox) mice exhibited recovery of mitochondrial proteins and DNA copy number, whereas gamma GT-Cre:ADRB2 (Flox/Flox) mice treated with formoterol did not. Analysis of mitochondrial morphology by transmission electron microscopy demonstrated that formoterol increased m itochondrial number and density in ADRB2 (Flox/Flox) mice but not in gamma GT-Cre:ADRB2( Flox/Flox) mice. These data demonstrate that proximal tubule beta(2) AR regulates renal mitochondrial homeostasis. Formoterol accelerates the recovery of renal function after AKI by activating proximal tubule beta(2) AR to induce mitochondrial biogenesis and demonstrates the overall requirement of RPTCs in renal recovery.