Formoterol Restores Mitochondrial and Renal Function after Ischemia-Reperfusion Injury

Abstract

Mitochondrial biogenesis may be an adaptive response necessary for meeting the increased metabolic and energy demands during organ recovery after acute injury, and renal mitochondrial dysfunction has been implicated in the pathogenesis of AKI. We proposed that stimulation of mitochondrial biogenesis 24 hours after ischemia/ reperfusion (I/R)-induced AKI, when renal dysfunction is maximal, would accelerate recovery of mitochondrial and renal function in mice. We recently showed that formoterol, a potent, highly specific, and long-acting b 2 -adrenergic agonist, induces renal mitochondrial biogenesis in naive mice. Animals were subjected to sham or I/Rinduced AKI, followed by once-daily intraperitoneal injection with vehicle or formoterol beginning 24 hours after surgery and continuing through 144 hours after surgery. Treatment with formoterol restored renal function, rescued renal tubules from injury, and diminished necrosis after I/R-induced AKI. Concomitantly, formoterol stimulated mitochondrial biogenesis and restored the expression and function of mitochondrial proteins. Taken together, these results provide proof of principle that a novel drug therapy to treat AKI, and potentially other acute organ failures, works by restoring mitochondrial function and accelerating the recovery of renal function after injury has occurred.

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

“…Mitochondrial dysfunction is commonly observed in acute organ injury of the kidney, heart, and liver (Di Lisa et al, 2007;Havasi and Borkan, 2011;Jaeschke et al, 2012). Recovery of renal structure and function following AKI has been reported to be accelerated through stimulation of MB by agonism of the b 2 -adrenergic receptor or by inhibition of cGMP-selective phosphodiesterases (Whitaker et al, 2013;Jesinkey et al, 2014). Likewise, stimulation of MB via agonism of the 5-HT 1F receptor with LY344864 herein was similarly able to promote accelerated renal recovery in an I/R-induced AKI model.…”

“…At the time of euthanasia, organs were harvested, snap-frozen in liquid nitrogen, and stored at 280°C. For the I/R model of acute kidney injury (AKI), mice were subjected to bilateral renal pedicle ligation as described previously (Zhuang et al, 2009;Jesinkey et al, 2014). In brief, renal artery and vein were isolated and blood flow was occluded with a vascular clamp for 18 minutes.…”

“…Stimulation of MB has been previously reported to accelerate the recovery of renal structure and function after AKI (Whitaker et al, 2013;Jesinkey et al, 2014). We examined the ability of LY344864 to stimulate MB and promote renal recovery in an I/Rinduced AKI model.…”

Mitochondria in Kidney Injury: When the Power Plant Fails

“…Notably, preservation of mitochondrial dynamics, prevention of mitochondrial membrane permeabilization, and/or promotion of mitochondrial biogenesis can protect kidney tubular cells and tissues in AKI. [6][7][8] As such, targeting the mitochondria has been proposed as a therapeutic strategy. Two studies 1,2 in this issue of the JASN have significantly advanced our understanding of the mitochondrial contribution to AKI.…”

“…MICOS, including mitofilin, preserves the cristae structure and regulates the activity of ATP synthase. The newly identified MA-5 binds to mitofilin to facilitate ATP generation via ATP synthase (Suzuki et al 8 ). (B) Upon stress, mitochondria become permeable at both MOM and MIM, leading to the release of cytochrome c, MPT, loss of membrane potential, inactivation of ATP synthase, and production of ROS for cell injury and death.…”