Abstract
Mitochondrial (Mt) dysfunction contributes to the pathophysiology of renal function and promotes cardiovascular disease such as hypertension. We hypothesize that renal Mt-genes derived from female spontaneously hypertensive rats (SHR) that exhibit hypertension have reduced expression specific to kidney cortex. After breeding a female Okamoto-Aoki SHR (SAP = 188mmHg) with Brown Norway (BN) males (SAP = 100 and 104 mmHg), hypertensive female progeny were backcrossed with founder BN for 5 consecutive generations in order to maintain the SHR mitochondrial genome in offspring that contain over increasing BN nuclear genome. Mt-protein coding genes (13 total) and nuclear transcription factors mediating Mt-gene transcription were evaluated in kidney, heart and liver of normotensive (NT: n = 20) vs. hypertensive (HT: n = 20) BN/SHR-mtSHR using quantitative real-time PCR. Kidney cortex, but not liver or heart Mt-gene expression was decreased ~2–5 fold in 12 of 13 protein encoding genes of HT BN/SHR-mtSHR. Kidney cortex but not liver mRNA expression of the nuclear transcription factors Tfam, NRF1, NRF2 and Pgc1α were also decreased in HT BN/SHR-mtSHR. Kidney cortical tissue of HT BN/SHR-mtSHR exhibited lower cytochrome oxidase histochemical staining, indicating a reduction in renal oxidative phosphorylation but not in liver or heart. These results support the hypothesis that renal cortex of rats with SHR mitochondrial genome has specifically altered renal expression of genes encoding mitochondrial proteins. This kidney-specific coordinated reduction of mitochondrial and nuclear oxidative metabolism genes may be associated with heritable hypertension in SHR.
Highlights
Hypertension constitutes a primary and significant factor in the development of cardiovascular disease
The nuclear trans-factors Tfam, NRF1, NRF2a, NRF2b and Pgc1a were all downregulated in the kidney, but not elsewhere, of HT Brown Norway (BN)/spontaneously hypertensive rats (SHR)-mtSHR
The renal mtRNA expression of mt-encoded cytochrome b was significantly reduced in hypertensive versus NT BN/SHR-mtSHR. mtCYB was reduced ~5 fold in HT BN/SHR-mtSHR (P = 0.0103) (Fig 2B)
Summary
Hypertension constitutes a primary and significant factor in the development of cardiovascular disease. Primary or essential hypertension is regarded as a multi-factorial disease, influenced by both genetic inheritance and environmental conditions that influence gene expression. The genetic basis of hypertension has been focused primarily on inheritance and expression of nuclear genes. Numerous trans-factors involved with mtDNA replication, transcription and mRNA processing are nuclear encoded, including mtRNA polymerase, mtDNA polymerase, several regulatory transcription factors and mtRNA processing proteins [2]. This nuclear-mitochondrial interaction is essential to cellular health and function, and may play a large role in the development of or response to cardiovascular disease [3]
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