Hypertension is a multifactorial disease that is marked by persistently high blood pressure. It is a risk factor for various cardiovascular disorders and can lead to stroke, myocardial infarction, etc. The polygenic nature of this disease makes it complex to understand its molecular mechanism. In this study, we first employ a function-dependent strategy to put forth that genes crucial for mitochondrial biogenesis may be involved in the pathogenesis of hypertension. We base this hypothesis on several studies that have established that mitochondrial dysfunction causes various forms of cardiovascular disorders. Expression profiling of various genes that mediated mitochondrial biogenesis reveals that these genes were differentially expressed in liver, brain, kidney, and left ventricular tissues of the Spontaneously Hypertensive Rat (SHR) vs. the Wistar Kyoto normotensive rat (WKY). Interestingly, we found that mitochondrial transcription factors (mtTFs, viz. Tfam, Tfb1m, and Tfb2m), are upregulated in the kidneys but downregulated in the left ventricle of SHR in contrast to WKY. Further, we uncover the plausible molecular mechanism of transcriptional regulation that could explain these differences.

We study the regulation of mitochondrial biogenesis and expression of mitochondrial transcription factors during hypoxic conditions and in rodent models of genetic hypertension. We report that the expression of HIF-1α (hypoxia inducible factor-1α), PGC-1α (peroxisome proliferator activated receptor-γ co-activator-1α), mtTFs and OXPHOS proteins are elevated in hypertensive rats as compared to their normotensive counterparts. Additionally, studies in cultured kidney epithelial cells show that acute hypoxia augments the expression of these genes. We also observe a positive correlation between HIF-1α and mtTFs transcripts in human tissues. Furthermore, we demonstrate for the first time to our knowledge, that HIF-1α binds to promoters of Tfam, Tfb1m and Tfb2m genes and augments their promoter activities in NRK-52e cells subjected to acute hypoxia. Taken together, this study provides evidence that acute hypoxia may enhance mitochondrial function to meet the energy demand in renal tubular epithelial cells and in young/pre-hypertensive SHR kidneys.

SHR are known to display impaired cardiac function and impaired cardiomyocyte mitochondrial morphology. Consistently, we demonstrate that the transcript levels of mtTFs, Pgc-1α, NRF1 and mitochondrially encoded genes are diminished in the left ventricle of SHR as compared to WKY. Using cultured cardiomyoblasts, we show that Tumor Necrosis Factor – alpha) TNF-α treatment leads to a decrease in mtTFs’ promoter activity, as well as mRNA and protein levels of mtTFs. These experiments were based on studies that have demonstrated that SHR have elevated systemic inflammation. Furthermore, we show that Ang-(1-7), a protective peptide of the Renin-Angiotensin-System, is able to rescue the TNF-α-induced transcriptional downregulation of mtTFs. Our experiments suggest that the YY1-PGC-1α complex might act as a molecular switch for the transcription of mtTFs in vitro.

To summarise, this study reports that kidney mitochondrial function in SHR might be augmented due to the hypoxic environment within renal epithelial cells. On the contrary, we show that inflammatory cues might be responsible for the diminished mitochondrial function and impaired ATP production in the left ventricle of SHR.