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

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: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, gGT-Cre:ADRB2^Flox/Flox mice had decreased renal cortical mRNA expression of the b₂AR. After IRI, formoterol treatment restored renal function in ADRB2^Flox/Flox but not gGT-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 gGT-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 gGT-Cre:ADRB2^Flox/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.