Mitochondrial biogenesis induced by the β2-adrenergic receptor agonist formoterol accelerates podocyte recovery from glomerular injury
| Autor: | Milos N. Budisavljevic, Rick G. Schnellmann, Michael G. Janech, Bushra Rahman, Pankaj Srivastava, Peifeng Deng, Deepak Nihalani, Ashish K. Solanki, Wayne R. Fitzgibbon, Justin B. Collier, Sang Ho Kwon, Ehtesham Arif, Michael R. Zile, Catalin F. Baicu, Judit Megyesi |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class 030232 urology & nephrology Apoptosis Article Podocyte Cell Line 03 medical and health sciences Mice 0302 clinical medicine Glomerulonephritis Downregulation and upregulation Formoterol Fumarate medicine Animals Humans Receptor Adrenergic beta-2 Receptor Agonists Organelle Biogenesis Chemistry Podocytes medicine.disease Actin cytoskeleton Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Mitochondria Disease Models Animal 030104 developmental biology medicine.anatomical_structure Mitochondrial biogenesis Nephrology Doxorubicin Gene Knockdown Techniques Formoterol Receptors Adrenergic beta-2 medicine.drug Signal Transduction |
| Zdroj: | Kidney Int |
| ISSN: | 1523-1755 |
| Popis: | Podocytes have limited ability to recover from injury. Here, we demonstrate that increased mitochondrial biogenesis, to meet the metabolic and energy demand of a cell, accelerates podocyte recovery from injury. Analysis of events induced during podocyte injury and recovery showed marked upregulation of peroxisome proliferator-activated receptor-γ coactivator–1α (PGC-1α), a transcriptional co-activator of mitochondrial biogenesis, and key components of the mitochondrial electron transport chain. To evaluate our hypothesis that increasing mitochondrial biogenesis enhanced podocyte recovery from injury, we treated injured podocytes with formoterol, a potent, specific, and long-acting β2-adrenergic receptor agonist that induces mitochondrial biogenesis in vitro and in vivo. Formoterol increased mitochondrial biogenesis and restored mitochondrial morphology and the injury-induced changes to the organization of the actin cytoskeleton in podocytes. Importantly, β2-adrenergic receptors were found to be present on podocyte membranes. Their knockdown attenuated formoterol-induced mitochondrial biogenesis. To determine the potential clinical relevance of these findings, mouse models of acute nephrotoxic serum nephritis and chronic (Adriamycin [doxorubicin]) glomerulopathy were used. Mice were treated with formoterol post-injury when glomerular dysfunction was established. Strikingly, formoterol accelerated the recovery of glomerular function by reducing proteinuria and ameliorating kidney pathology. Furthermore, formoterol treatment reduced cellular apoptosis and increased the expression of the mitochondrial biogenesis marker PGC-1α and multiple electron transport chain proteins. Thus, our results support β2-adrenergic receptors as novel therapeutic targets and formoterol as a therapeutic compound for treating podocytopathies. |
| Databáze: | OpenAIRE |
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