Sustained mitochondrial dysfunction in male, but not female Spontaneous Hypertensive Rats (SHR) corresponds with delayed renal recovery from ischemic injury

Abstract

Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in hospital settings with high mortality rates. The mechanisms mediating renal IR injury and leading to increased risk of later developing cardiovascular and renal diseases in either sex remain poorly understood. We previously reported that there is sex difference in renal recovery from IR where males have a delayed recovery vs females. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of AKI in males, resulting in abnormal kidney repair and disease progression. However, the impact of IR on mitochondrial function in females has not been examined. The goal of the current study was to test the hypothesis that IR results in greater sustained mitochondrial dysfunction in males vs. females corresponds to delayed recovery of renal function in males. 13-week-old male and female SHR were subjected to sham or 30-minute warm bilateral IR. Subsets of rats were euthanized 1- or 7-days post-IR (n=6/group). Blood was collected to measure kidney function. The right kidney was dissected and processed for electron microscopy (EM) to assess mitochondrial structure, histological analysis of renal structure, and measurement of mitochondrial DNA (mtDNA) copy number via RT-PCR. Tubular cells were isolated from the left kidney to measure oxygen consumption rate (OCR) to assess mitochondrial respiration using Seahorse XFe24 Extracellular Flex Analyzer. IR increased plasma creatinine (Pcr) in male and female SHR vs. respective sham controls 1-day post-IR (PIR =0.0001; Psex✕IR=0.2). Pcr remained elevated in male, but not female, SHR 7 days post-IR (Pcr: PIR =0.03; Psex✕IR=0.04). OCR was reduced in male and female tubules 1 day post IR (PIR =0.001; Psex=0.94) and remained reduced only in tubules from males 7 days post-IR (PIR =0.0001; Psex✕IR=0.0001). Consistent with decreased OCR, EM revealed swollen round mitochondria, reduced mitochondria density with complete loss of cristae membranes vs. sham controls 1-day post-IR in both sexes, which was sustained 7 days post-IR only in males. Mitochondrial DNA copy number and peroxisome proliferator-activator receptor-y coactivator (PGC-1α) mRNA expression was also reduced 1-day post-IR in both sexes (PIR =0.05; Psex✕IR=0.59) and remained down only in males 7 days post-IR (PIR =0.02; Psex✕IR=0.001). In conclusion, our data demonstrate that there is sex difference in mitochondria after renal IR. Males have sustained mitochondrial dysfunction with delayed renal recovery compared to females. Further studies will be carried out to better understand the direct impact of mitochondria dysfunction on renal recovery post-IR in male and females. This work was supported by career development grant from AHA (20CDA35310362) to R Mohamed; National Institutes of Health (1P01HL134604-01 and R01 HL127091 to J. C. Sullivan. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.