Renal Specific Downregulation of OXPHOS Transcription Factors and Mitochondrial Respiratory Dysfunction in Spontaneously Hypertensive Nonhuman Primates
Authors: Goleva Slavina , Rhoads Megan , Osborn Jeffrey 
Published: November 2023

The African Green Monkey (Chlorocebus aethiops sabaeus; AGM) exhibits heritable, spontaneous hypertension and shares a closely related genome and phylogeny with humans. Thus, the AGM is a novel, translational model for the study of human essential hypertension. We previously determined that gene expression of SDH, a nuclear oxidative phosphorylation (OXPHOS)‐encoding gene, was upregulated 2‐fold in the renal outer medulla (OM) of hypertensive (HT) compared with normotensive (NT) AGM, but was not different in the inner medulla (IM) and cortex. Nuclear OXPHOS‐encoding gene COX4 was downregulated 2‐fold in renal OM and IM of HT AGM, but was not different in cortex. We hypothesize that gene expression of nuclear transcription factors TFAM (which regulates the expression of nuclear OXPHOS genes) and NRF2 (which regulates transcription of TFAM and anti‐oxidant proteins) are altered in renal OM and IM of HT AGM. Taken together, this may elicit renal respiratory mitochondrial dysfunction in HT AGM. AGM were phenotyped as NT (systolic blood pressure <120 mmHg; SBP) or HT (SBP > 140 mmHg). Gene expression was determined using semi‐quantitative RT‐PCR using kidney cortical, OM, and IM RNA extracted from 18 HT (SBP=166±7 mmHg) and 18 NT (SBP=98±3 mmHg) AGM. TFAM gene expression was downregulated 3‐fold in renal OM (p<0.05) but unchanged in IM and cortex of HT vs. NT AGM. NRF2 gene expression was downregulated 2‐fold in renal OM (p<0.05) and 3‐fold in IM (p<0.05) of HT AGM, but was not different in cortex. Thus, OXPHOS dysfunction in AGM and increased oxidative stress in kidneys of HT AGM may occur due to a diminished presence of anti‐oxidant proteins and OXPHOS‐encoding genes. To assess OXPHOS dysfunction in HT vs. NT AGM, frozen renal cortex and OM were sectioned from HT (SBP=185±11 mmHg; n=4) and NT (SBP=99±4 mmHg; n=4) AGM and mitochondrial respiratory function was visualized using COX/SDH double‐labeling histochemistry. A novel program (SpectrumAnalyst) was developed to semi‐quantitate the relative mitochondrial dysfunction in each tissue section image as a percentage of the total tissue area. Preliminary SDH/COX analysis shows that HT AGM have greater mitochondrial respiratory dysfunction (17±3.7%) relative to NT AGM (7±2.4%) in renal cortex, but there is no difference in mitochondrial respiratory function between NT and HT AGM in renal OM. Taken together, gene expression differences of nuclear OXPHOS‐encoding genes in renal OM of HT AGM may be masked by post‐translational protein modifications that preserve mitochondrial respiratory function. SDH/COX staining indicates that OXPHOS dysfunction may be present in renal cortex of HT AGM, and RT‐qPCR results suggest that this is not due to OXPHOS‐encoding gene expression differences. Rather, renal cortical OXPHOS dysfunction may be due to post‐translational modifications in HT vervets (e.g. increased oxidative stress) that ultimately alter long‐term control of renal function and blood pressure.Support or Funding InformationSupported by APS; Biomedical Science Research Group, LLC; Telabio, Inc; Behavioral Sciences Foundation; and University of Kentucky Honors Program