Abstract P2042: Alteration of Mitochondrial Deoxyribonucleic Acid Methylation and Nuclear Transcription Factors Reduces Mitochondrial Biogenesis in Aged Hypertensive Kidney

Abstract

Accumulating evidence suggests that epigenetic mechanisms contribute to aging and target organ injury during hypertension. Aberrant DNA methylation of mitochondrial genes can affect mitochondrial copy numbers, replication and metabolism. Recently, the presence of mitochondrial DNA (mtDNA) methylation was reported; however, its functional significance in aging and hypertension-induced chronic kidney disease is unknown. We hypothesized that alteration in mtDNA methylation aggravates hypertension injury in aged kidney by disrupting mitochondrial homeostasis leading to reduced mitochondrial biogenesis and dysfunction. Hydrogen sulfide (H 2 S) was shown to modulate chromatin recently, we therefore investigated whether H 2 S can act as an epigenetic modifying agent to protect renal mitochondria and improve renal function. Aged (72-75 weeks) and young (10-12 weeks) wild type (WT, C57BL/6J) mice were treated without or with angiotensin-II (Ang II, 1000 ng/Kg/d) and H 2 S donor, GYY4137 (0.5 mg/Kg/d, i.p.), for 28 d. Ang-II increased mean blood pressure in aged mice compared to young (136.54±3.55 vs. 108.68±2.86 mmHg) and reduced glomerular filtration rate (688.3±24.83 vs. 1029.3±30.8 μL/min/100 g b.w.). H 2 S treatment reduced mean BP (122.34±3.47) and increased GFR (962.7±21.5) in aged mice receiving Ang II. In aged mice, querying renal mitochondrial genes for methylation status revealed increased methylation of mt-ND1 and reduction of mt-CO1 and mt-CO2 and H 2 S treatment reversed the changes. Methylation of mt-Cytb was undetected and mt-Dloop was low in Ang II treated aged mice and increased with H 2 S treatment. Ang II treated aged mice exhibited decreased PGC-1α and nuclear transcription factors, NRFI, NRF2, ERRα and TFAM, indicating reduced mitochondrial biogenesis compared to young mice and H 2 S restored their levels. ATP synthase activity, ATP generation was reduced in aged mice receiving Ang II compared to young and increased with H 2 S treatment. Together, our results suggest that alteration in mtDNA methylation and impaired nuclear DNA genes is associated with reduced mitochondrial replication and disrupted metabolism and H 2 S therapy protects the aged kidney from hypertension-induced damage by restoring mitochondrial homeostasis.