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Kidney Week

Abstract: PO0897

The β2-Adrenergic Receptor Agonist Formoterol Restores Mitochondrial Dynamics and Energy Production in the Diabetic Renal Proximal Tubule

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Cleveland, Kristan H., University of Arizona, Tucson, Arizona, United States
  • Brosius, Frank C., University of Arizona, Tucson, Arizona, United States
  • Schnellmann, Rick G., University of Arizona, Tucson, Arizona, United States
Background

While diabetic kidney disease (DKD) is the leading cause of end stage renal disease, the early pathophysiology of this disease remains poorly understood. In type 2 diabetes mitochondrial dysfunction and changes in energy metabolism occurs in proximal tubules. We examined the effects of formoterol, a β2-adrenergic receptor (AR) agonist previously demonstrated to induce mitochondrial biogenesis and promote recovery from acute kidney injury, on renal mitochondrial homeostasis and energy production in diabetic db/db mice and in renal proximal tubule cells (RPTC) treated with high glucose.

Methods

RPTC from rabbits were isolated using the iron oxide perfusion method and grown in 0 glucose, 17mM glucose or 17mM mannitol as an osmotic control for 96 hr. ATP, uncoupled oxygen consumption rate (OCR) and mitochondrial dynamics and energetics proteins were measured. Db/db and nondiabetic db/m control mice were treated with either vehicle or formoterol (1mg/kg, i.p.) daily for three weeks beginning at 10 weeks of age. At 13 weeks, kidneys were harvested and changes in mitochondrial proteins were measured.

Results

RPTC treated with glucose for 96 hr exhibited a decrease in ATP, uncoupled OCR and the mitochondrial fusion protein Mfn1. In contrast, the fission protein pDrp1 and electron transport chain (ETC) complexes I-V increased. Treatment with formoterol (30nM) restored ATP, Mfn1, pDrp1 and ETC complex proteins to control levels. Similarly, vehicle treated db/db mice exhibited increases in ETC protein complexes I, II, III and V, and pDrp1 in renal cortex. Diabetic mice showed a decrease in Mfn1 in renal cortex. Formoterol restored complexes I, II, III and V, pDrp1 and Mfn1 to control levels in db/db mice. ATP was decreased in db/db mice and was restored to control levels with formoterol treatment.

Conclusion

Together, these in vivo and in vitro results suggest that increased glucose alters mitochondria dynamics (increase fission/decrease fusion) and decreases ATP in spite of increased ETC proteins. Formoterol reverses these glucose-induced effects and may be used as a potential therapy to prevent early disease progression of DKD.

Funding

  • NIDDK Support