Regulation of mitochondrial dynamics and energetics in the diabetic renal proximal tubule by the β2-adrenergic receptor agonist formoterol

Kristan H. Cleveland, Frank C. Brosius, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Diabetes is a prevalent metabolic disease that contributes to ∼50% of all endstage renal disease and has limited treatment options. We previously demonstrated that the β2-adrenergic receptor agonist formoterol induced mitochondrial biogenesis and promoted recovery from acute kidney injury. Here, we assessed the effects of formoterol on mitochondrial dysfunction and dynamics in renal proximal tubule cells (RPTCs) treated with high glucose and in a mouse model of type 2 diabetes. RPTCs exposed to 17 mM glucose exhibited increased electron transport chain (ETC) complex I, II, III, and V protein levels and reduced ATP levels and uncoupled oxygen consumption rate compared with RPTCs cultured in the absence of glucose or osmotic controls after 96 h. ETC proteins, ATP, and oxygen consumption rate were restored in RPTCs treated with formoterol. RPTCs exposed to high glucose had increased phosphodynamin- related protein 1 (Drp1), a mitochondrial fission protein, and decreased mitofusin 1 (Mfn1), a mitochondrial fusion protein. Formoterol treatment restored phospho-Drp1 and Mfn1 to control levels. Db/db and nondiabetic (db/m) mice (10 wk old) were treated with formoterol or vehicle for 3 wk and euthanized. Db/db mice showed increased renal cortical ETC protein levels in complexes I, III, and V and decreased ATP; these changes were prevented by formoterol. Phospho-Drp1 was increased and Mfn1 was decreased in db/db mice, and formoterol restored both to control levels. Together, these findings demonstrate that hyperglycemic conditions in vivo and exposure of RPTCs to high glucose similarly alter mitochondrial bioenergetic and dynamics profiles and that treatment with formoterol can reverse these effects. Formoterol may be a promising strategy for treating early stages of diabetic kidney disease.

Original languageEnglish (US)
Pages (from-to)F773-F779
JournalAmerican Journal of Physiology - Renal Physiology
Volume319
Issue number5
DOIs
StatePublished - Nov 2020

Keywords

  • Diabetic kidney disease
  • Electron transport chain
  • Mitochondria
  • Mitochondrial dynamics
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint

Dive into the research topics of 'Regulation of mitochondrial dynamics and energetics in the diabetic renal proximal tubule by the β2-adrenergic receptor agonist formoterol'. Together they form a unique fingerprint.

Cite this