Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis

Abstract

Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.2-fold) 1 and 2 d after injection that resolved by 4 d. In contrast, peroxisome proliferator gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated ~80% 1 d after FA injection and remained depressed through 14 d. Multiple electron transport chain and ATP synthesis genes were also down-regulated from 1–14 d after FA, including NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUFβ8), ATP synthase subunit β (ATPS-β), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced ~50% from 2–14 d after FA injection. Protein levels of early fibrosis markers α-smooth muscle actin and transforming growth factor β1 were elevated at 6 and 14 d after FA. Picro-sirius red staining and collagen 1A2 (COL1A2) IHC revealed staining for mature collagen deposition at 14 d. We propose that mitochondrial dysfunction induced by AKI is a persistent cellular injury that promotes progression to fibrosis and CKD, and that this model can be used to test mitochondrial therapeutics that limit progression to fibrosis and CKD.

Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4–Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

“…Mitochondrial turnover is regulated by a complex interplay between fission/ fusion, autophagy/mitophagy, and MB (Gottlieb and Gustafsson, 2011;Stallons et al, 2013). Our laboratory and others have recently demonstrated alterations in MB in experimental models of AKI (Weinberg, 2011;Funk and Schnellmann, 2012;Jesinkey et al, 2014;Stallons et al, 2014). MB is tightly controlled by the PGC-1 family of transcriptional coactivators including PGC-1a, PGC-1b, and PRC which coordinate both nuclear and mitochondrial responses to increase cellular mitochondrial content.…”

Progression after AKI

“…Development of fibrosis in the folic acidinduced AKI model was associated with suppression of mitochondrial biogenesis. 39 Moreover, epigenetic alterations can be activated after kidney injury, including histone modifications, DNA methylation, and chromosomal conformational changes that regulate gene expression. There have been studies showing that histone deacetylase inhibitors accelerate recovery and decrease postinjury fibrosis after I/R 40 and aristolochic acid nephrotoxicity, 41 suggesting that epigenetic changes may influence the transition of AKI to CKD.…”

Renal Fibrosis and Mitochondrial Biogenesis

“…16,[19][20][21][22] Recently increasing evidences showed mitochondrial dysfunction in a broad spectrum of pathogenesis of renal diseases. Moreover renal diseases patients exhibited an impaired mitochondrial respiratory system.…”

“…Tubular epithelial cell damage causes from apoptosis/necrosis and epithelial-mesenchymal transition, additionally, endothelial dysfunction causes from apoptosis/necrosis and endothelial-mesenchymal transition. 18,19,[21][22][23][24][25][26] Studies have shown significantly increased ROS production, up-regulation of TGF-β expressions, high glucose levels, proteinuria, uremic toxins, ischemia/hypoxia, and activation of RAAS in peripheral blood mononuclear cells of patients, thereby demonstrating the close association between mitochondrial dysfunction and renal diseases progression. 21,25,27,28 Recently, a number of studies have revealed that regulation of co-activators can physiologically signal to specific transcription factor targets.…”

“…They are also involved in the expression of mitochondrial transcription and replication factors. 17,19,21,25,[29][30][31] Nuclear respiratory factor-1 (NRF-1), a major transcription factor in the human genome, plays a key regulatory role in mitochondrial biogenesis. Initially, NRF-1 was identified as being responsible for regulating genes involved in mitochondrial respiratory function.…”