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

Authors: Cleveland, Kristan H; Brosius 3rd, Frank C; Schnellmann, Rick G

Published In Am J Physiol Renal Physiol, (2020 Nov 01)

Abstract: Diabetes is a prevalent metabolic disease that contributes to ∼50% of all end-stage 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 phospho-dynamin-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.

PubMed ID: 32954853

MeSH Terms: Adrenergic Agonists/pharmacology*; Animals; Disease Models, Animal; Formoterol Fumarate/metabolism*; Kidney Tubules, Proximal/drug effects*; Kidney Tubules, Proximal/metabolism; Kidney/drug effects; Kidney/metabolism; Mice; Mitochondria/drug effects*; Mitochondria/metabolism; Mitochondrial Dynamics/drug effects*; Mitochondrial Proteins/metabolism; Organelle Biogenesis