Regulation of mitochondrial dynamics and energetics in the diabetic renal proximal tubule by the β2-adrenergic receptor agonist formoterol
Regulation of mitochondrial dynamics and energetics in the diabetic renal proximal tubule by the β2-adrenergic receptor agonist formoterol
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DOI：
10.1152/ajprenal.00427.2020
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发表时间：
2020-11-01
影响因子：
4.2
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
--
作者：
Cleveland, Kristan H.;Brosius, Frank C., III;Schnellmann, Rick G.
糖尿病是一种普遍的代谢性疾病，约占所有终末期肾病的 50%，且治疗选择有限。我们之前证明β(2)-肾上腺素能受体激动剂福莫特罗诱导线粒体生物合成并促进急性肾损伤的恢复。在这里，我们评估了福莫特罗对高糖处理的肾近端小管细胞 (RPTC) 和 2 型糖尿病小鼠模型中线粒体功能障碍和动力学的影响。与在没有葡萄糖或渗透压控制的情况下培养的 RPTC 相比，96 小时后，暴露于 17 mM 葡萄糖的 RPTC 表现出电子传递链 (ETC) 复合物 I、II、III 和 V 蛋白水平增加，ATP 水平和解偶联耗氧率降低。在用利莫特罗处理的 RPTC 中，ETC 蛋白、ATP 和耗氧率得到恢复。暴露于高葡萄糖的 RPTC 增加了磷酸动力相关蛋白 1 (Drp1)（一种线粒体裂变蛋白），并减少了线粒体融合蛋白 1 (Mfn1)（一种线粒体融合蛋白）。福莫特罗治疗使磷酸化 Drp1 和 Mfn1 恢复至对照水平。 Db/db 和非糖尿病 (db/m) 小鼠（10 周龄）用福莫特罗或载体治疗 3 周并安乐死。 Db/db 小鼠表现出复合物 I、III 和 V 中肾皮质 ETC 蛋白水平升高，ATP 降低；福莫特罗可以阻止这些变化。 db/db 小鼠中 Phospho-Drp1 增加，Mfn1 减少，福莫特罗将两者恢复至对照水平。总之，这些发现表明，体内高血糖条件和 RPTC 暴露于高葡萄糖同样会改变线粒体生物能和动力学特征，而福莫特罗治疗可以逆转这些影响。福莫特罗可能是治疗早期糖尿病肾病的一种有前途的策略。
Diabetes is a prevalent metabolic disease that contributes to similar to 50% of all endstage renal disease and has limited treatment options. We previously demonstrated that the beta(2)-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 lbrmoterol. 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.