Journal
KIDNEY INTERNATIONAL
Volume 96, Issue 3, Pages 656-673Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2019.03.023
Keywords
albuminuria; focal segmental glomerulosclerosis; glomerulus; glomerulonephritis; podocyte
Categories
Funding
- NIH [2R01DK087956-06A1, R56 DK116887-01A1, GM084147]
- Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [BX-000851]
- American Society of Nephrology
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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-g coactivator-1 alpha (PGC-1 alpha), 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 beta 2-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, beta 2-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-1 alpha and multiple electron transport chain proteins. Thus, our results support beta 2-adrenergic receptors as novel therapeutic targets and formoterol as a therapeutic compound for treating podocytopathies.
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