Abstract: FR-PO177

The Role of Gβγ-Dependent Signaling in Formoterol-Induced Mitochondrial Biogenesis and Recovery of Renal Function in Mice

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Cameron, Robert Bruce, Medical University of South Carolina, Charleston, South Carolina, United States
  • Collier, Justin B., Medical University of South Carolina, Charleston, South Carolina, United States
  • Schnellmann, Rick G., University of Arizona, Tucson, Arizona, United States
Background

Acute kidney injury (AKI) is prevalent and has substantial morbidity and mortality with few effective therapies. AKI is associated with the activation of kinases, such as ERK1/2, that prolong injury and prevent recovery. Our laboratory has recently shown that ERK1/2 activation suppresses mitochondrial function and induces KIM-1 expression following AKI in mice. Formoterol, a β2 adrenoceptor agonist, accelerates recovery of renal function in mouse models of AKI. However, the effects of formoterol on signaling in healthy and injured kidney are unknown.

Methods

Male C57BL/6 mice received DMSO or 0.3 mg/kg formoterol i.p. and were euthanized at 30 min or 24 h. For inhibitor studies, mice received gallein (an inhibitor of the G protein heterodimer Gβγ) 1 h prior to formoterol or diluent control. To model the effects of formoterol on AKI, mice were subjected to bilateral ischemia-reperfusion (IR) injury and received formoterol 24 h following surgery. Injured and sham mice were euthanized 30 min and 24 h following formoterol administration.

Results

Formoterol increased Akt phosphorylation and cGMP in the renal cortex at 30 min following treatment. At 24 h, formoterol increased expression of the mitochondrial protein ATP synthase beta (ATPSβ), a marker of mitochondrial biogenesis (MB). The increases in Akt phosphorylation and ATPSβ were blocked by pretreatment with gallein. Following IR injury, formoterol accelerated recovery of renal function as measured by blood urea nitrogen (BUN) and serum creatinine (SCr) at 24 h following formoterol administration. This was accompanied by a decrease in renal injury as measured by KIM-1 expression in the renal cortex. At 30 minutes following formoterol administration after I/R, the phosphorylation of ERK1/2 was reduced compared to mice treated with vehicle.

Conclusion

In the healthy kidney, formoterol activates Gβγ-Akt dependent signaling to upregulate mitochondrial proteins and biogenesis. Following injury, formoterol has rapid effects on renal recovery, in part through modulation of ERK1/2. Modulation of Gβγ-dependent signaling and MB by formoterol may provide novel therapeutics for AKI.

Funding

  • NIDDK Support