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 β (2)-adrenergic receptor (β (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 β (2)AR (γGT-Cre:ADRB2(Flox/Flox)). These mice and wild-type controls (ADRB2(Flox/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 ADRB2(Flox/Flox) mice, γGT-Cre:ADRB2(Flox/Flox) mice had decreased renal cortical mRNA expression of the β (2)AR. After IRI, formoterol treatment restored renal function in ADRB2(Flox/Flox) but not γGT-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 γGT-Cre:ADRB2(Flox/Flox) mice treated with formoterol did not. Analysis of mitochondrial morphology by transmission electron microscopy demonstrated that formoterol increased mitochondrial number and density in ADRB2(Flox/Flox) mice but not in γGT-Cre:ADRB2(Flox/Flox) mice. These data demonstrate that proximal tubule β (2)AR regulates renal mitochondrial homeostasis. Formoterol accelerates the recovery of renal function after AKI by activating proximal tubule β (2)AR to induce mitochondrial biogenesis and demonstrates the overall requirement of RPTCs in renal recovery.