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

Abstract

Acute kidney injury (AKI) is the transient loss of renal function following an insult, such as nephrotoxicant exposure, sepsis, or ischemia. Numerous cell types play a role in the pathogenesis of AKI, including immune, endothelial, and renal proximal tubule cells. Our laboratory demonstrated that the beta‐2 adrenergic receptor (ADRB2) agonist formoterol accelerates the recovery of renal and mitochondrial function in mice following ischemia‐reperfusion injury (IRI). However, the cell type(s) responsible for this recovery remains unknown. To assess the role of renal proximal tubule cells in formoterol‐induced recovery of renal function, we generated a proximal tubule‐specific knockout of the ADRB2 receptor (γGT‐Cre: ADRB2Flox/Flox). Compared to controls (ADRB2Flox/Flox), renal cortical mRNA expression of the ADRB2 receptor was decreased 90% in γGT‐Cre:ADRB2Flox/Flox mice. These mice were subjected to renal IRI, followed by once daily dosing with 0.3 mg/kg formoterol or vehicle beginning at 24 h and euthanasia at 144 h. At 24 h following IRI, ADRB2Flox/Flox and γGT‐Cre: ADRB2Flox/Flox mice had a similar loss of renal function as measured by serum creatinine (0.89 mg/dL and 0.86 mg/dL, respectively). At 144 h following IRI, both ADRB2Flox/Flox and γGT‐Cre:ADRB2Flox/Flox mice treated with vehicle exhibited a modest but incomplete recovery of renal function as measured by serum creatinine (0.43 mg/dL and 0.46 mg/dL, respectively). These mice had similarly suppressed renal cortical mRNA and protein expression of markers of mitochondrial homeostasis such as NDUFB8, COX1, ATPSβ, and Mfn2. Following treatment with formoterol, ADRB2Flox/Flox mice exhibited accelerated recovery of renal function as measured by serum creatinine (0.20 mg/dL) with associated rescue of mitochondrial markers in the renal cortex. In contrast, formoterol did not enhance the recovery of renal function as measured by serum creatinine (0.39 mg/dL) or mitochondrial markers in γGT‐Cre:ADRB2Flox/Flox mice subjected to IRI. These data reveal that formoterol‐induced ADRB2 receptor activation on proximal tubule cells induces mitochondrial biogenesis and restores renal function following AKI. Support or Funding Information R.B.C. is supported by F30 DK104550 and T32 GM008716 (National Institutes of Health). W.S.G. is supported by T32 DK083262. R.G.S. is supported by R01 GM084147 (National Institutes of Health) and 1BX000851 (Department of Veterans Affairs). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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