Hypoxia-mediated regulation of mitochondrial transcription factors: Implications for hypertensive renal physiology

Abstract

Abbreviations mtTFs, mitochondrial transcription factors; OXPHOS, oxidative phosphorylation; ATP, adenosine triphosphate; ETC, electron transport chain, TiH, tubulointerstitial hypoxia; PGC-1αperoxisome proliferator activated receptor gamma coactivator 1-alpha; SHR, spontaneously hypertensive rats; WKY, Wistar Kyoto rat; HIF-1α, Hypoxia Inducible factor 1α; HREs, hypoxia response elements; mtDNA, mitochondrial DNA; ChIP, chromatin immunoprecipitation; bp, base pair. AbstractIntroduction: Kidneys are organs with high resting metabolic rate and low tissue pO 2 due to enhanced mitochondrial oxygen consumption and ATP production for active solute transport.Such enhanced mitochondrial activity leads to progressive hypoxia from the renal cortex to medulla. Renal tubulointerstitial hypoxia (TiH) is severe in hypertensive rats due to increased sodium reabsorption within their nephrons. However, expression of mitochondrial transcription factors (mtTFs) (viz. Tfam, Tfb1m and Tfb2m) and mitochondrial biogenesis is not reported during hypoxic conditions. Materials and Methods:Transcriptional regulation of Tfam, Tfb1m and Tfb2m under acute hypoxia was studied using promoter-driven luciferase assays, qPCR, western blotting and Chromatin Immunoprecipitation. Results:The expression of HIF-1α, PGC-1α, Tfam, Tfb1m, Tfb2m and OXPHOS proteins were higher in hypertensive rats as compared to the normotensive ones. Additionally, studies on NRK52e cells show that acute hypoxia increases the expression of these genes. We also observed a positive correlation between HIF-1α and mtTFs in human tissues. Furthermore, we report for the first time, that HIF-1α binds to promoters of Tfam, Tfb1m and Tfb2m genes and augments their promoter activity.Conclusion: Hypertensive rats, with increased TiH show enhanced expression of mitochondrial proteins. HIF-1α directly binds to and increases promoter activity of mtTFs.Acute hypoxia induces the expression of mtTFs and probably promotes mitochondrial biogenesis in NRK52e cells.