Sex differences (biological distinctions between males and females) present a complex interplay of genetic, developmental, biological, and environmental factors. More and more studies are shedding light on importance of sex differences in normal physiology and susceptibility to cancer, cardiovascular and renal conditions, and neurodegenerative diseases. This mini-review is devoted to the role of sex dimorphisms in renal function, with a focus on the distinctions between male and female mitochondria. Here, we cover the aspects of renal mitochondrial bioenergetics where sex differences have been reported to date, for instance, biogenesis, reactive oxygen species production and oxidative stress. Special attention is devoted to the effects of sex hormones, such as estrogen and testosterone, on mitochondrial bioenergetics in the kidney in physiology and pathophysiology.

Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 μg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 lg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 lg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.

Introduction Sex differences are implicated in many cardiovascular and renal pathologies; for instance, premenopausal females are typically less prone to renovascular damage than males. However, although mitochondrial bioenergetics per se is a well‐known factor that can mediate the progression of the renal diseases, it is not known if there are sex‐related dissimilarities in the performance of renal mitochondria prior to the development of any disease. The goal of this study was to test the differences in renal cortical and medullary mitochondrial function in healthy male versus female rats. Methods . Mitochondria were isolated from the kidneys collected from male and female Sprague Dawley (SD) rats procured from Charles River labs at 11 weeks of age. Mitochondrial membrane potential, superoxide and H2O2 levels were measured with luminescent or fluorescent dyes (TMRM, MCLA and Amplex Red) in mitochondria isolated from renal cortex and medulla. To measure the oxygen consumption rate (OCR) and mitochondrial calcium uptake, seahorse assay and spectrofluorimetry with CaGreen dye, respectively, were performed on isolated mitochondria. Lipid peroxide radical formation was detected using electron spin resonance spectroscopy (ESR) with in vivo spin trapping. The SOD activity and total antioxidant capacity were measured using commercially available kits. In order to analyze the expression levels of various mitochondria‐related proteins, Western blot analysis was performed on snap‐frozen isolated renal mitochondria. Results . Kidneys from SD male (SDM) and female rats (SDF) were divided into cortex (SDMC, FC) and medulla (SDMM, FM). We report higher membrane potential in SDFM compared to SDMM (p<0.001). H2O2 levels were elevated in both the SDFC and SDFM mitochondria compared to SDM (p<0.01), and GPX4 level was significantly increased the SDFM samples. Interestingly, superoxide production was increased in the medulla compared to the cortex for both SDM and SDF, while SOD2 expression was similar. Total SOD activity was increased in SDFC compared to all other groups (p<0.01). ESR showed similar lipid peroxide radical levels in all groups. Antioxidant capacity was reduced in SDFM tissues compared to other groups (p<0.05). Female mitochondria exhibited decreased OCR compared to males, and all OCR parameters were lower in medullary vs cortical mitochondria, independent of sex. Interestingly, calcium uptake was more active in the medulla vs cortex for both males and females, whereas the mitochondrial permeability transition pore (mPTP) opening was recorded earlier in females than males. Conclusions . We report differences in mitochondrial function in the cortex and medulla of young healthy male and female rats, primarily, in their ability to handle reactive oxygen species. The observed sex‐related dissimilarities open new avenues of research aimed at establishing the mechanisms that may affect the predisposition of males and females to kidney disease development later in life.

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