Gonadectomy Effects on Renal Function in Wistar Rats of Both Sexes

Abstract

The role played by sex hormones in kidney function is not fully understood. The earlier studies with stilbestrol administration (synthetic estrogen) evidenced reduced sodium and water excretion, which could predispose to the development of arterial hypertension (1). However, more recently estradiol has been demonstrated to improve renal function by stimulating nitric oxide (NO) synthesis and modulating renal hemodynamic (2, 3). Testosterone (the main male steroid hormone), was suggested to exert a vascular effect on the kidneys by increasing sensitivity to vasoconstrictor agents (4), as well as negatively modulating the NO synthesis (5). Furthermore, sexual hormones are among the factors playing an important role in the progression of kidney disease, a disorder that affects a large number of people worldwide (6-8). The chronic kidney disease is more common in women; however, men are more likely to develop end-stage renal disease. Several theories attempt to explain the discrepancy in the incidence of chronic kidney disease and end-stage renal disease between men and women (6-8). Detailed investigation of renal function parameters in both sexes can help to clarify the physiological differences between men and women and to understand the evolution of the disease. Objective: To evaluate renal function parameters in male and female Wistar rats submitted or not to gonadectomy. Methods: Two-month-old Wistar rats underwent gonadectomy or sham surgery (Sham), composing four experimental groups: Sham male (SM), Sham female (SF), gonadectomized males (GM) and gonadectomized females (GF). They were kept in collective cages under appropriate conditions. At 6 months of age, blood pressure (BP) and body weight (BW) were assessed. The animals were then placed in metabolic cages to collect 24-hour urine samples to assess creatinine, protein and electrolyte excretion. Blood was also collected from the tail vein to evaluate plasma concentrations of sodium, potassium, urea and creatinine. CEUA/UNIFESP: 9009241022. Results presented as mean ± standard error; Two-way ANOVA followed by Tukey test, p<0.05. Results: Female rats had lower body weight when compared to male rats following the sexual pattern for rats (SM:462.8±9.2, GM:423.4±29.5, SF:284.9±6.7, GF:323.9± 9.9, g, psex<0.0001). Gonadectomized animals, both males and females, had a decreased kidney/body mass ratio (SM: 0.70±0.02, GM:0.60±0.01g, SF:0.74±0.03, GF:0.65±0.02, %, pgonadectomy=0.0010) showing impairment in renal development after the surgery. Regarding systolic blood pressure, no significant difference was observed between the groups (SM: 126±2.1, GM: 123±1.5, SF: 126±2.5, GF: 129±2.4, mmHg), however, the GF group presented blood pressure values close to the normal superior limit, confirming that in females the absence of female hormones increases the probability of developing arterial hypertension. Regarding the glomerular filtration rate (GFR) assessed by creatinine clearance, we found that gonadectomy had a negative impact on females, but not on males (SM: 6.3±0.5, GM: 6.3±0.7, SF: 5.6±0.5, GF: 4.1±0.2, mL·min−1·kg−1, psex=0.0045). Moreover, the group of normal males (SM) presented greater proteinuria (SM: 12.8±0.9, GM: 1.5±0.2, SF: 2.9±0.2, GF: 3.4±0.4, mg/24h, psex<0.0001, pgonadectomy<0.0001, pinteraction<0.0001), a fact not observed after gonadectomy, highlighting the influence of testosterone on glomerular function. No changes were observed in urinary excretion of sodium and potassium and in plasma levels of urea and sodium. The mean glomerular area was greater in males compared to females, whether gonadectomized or not (SM: 10,608±270, GM: 10,123±462, SF: 7,616±370, GF: 7,945±374, μm2, psex<0.0001). In humans, it is not yet well defined whether there is dimorphism in relation to the glomerular area, but many experimental studies indicate a greater glomerular area in males, as observed in the present study (9). These preliminary results suggest that in female rats the deprivation of sexual hormones after gonadectomy appears to negatively interfere with renal function. However, the same did not happen after gonadectomy in males. More studies are needed to understand the mechanisms involved in these effects. 1. Christy NP, Shaver JC. Estrogens and the kidney. Kidney Int. 1974; 6(5):366-76. 2. Raij L, Baylis C. Glomerular actions of nitric oxide. Kidney Int. 1995; 48(1):20-32. 3. Carlström M, et al. Renal autoregulation in health and disease. Physiol Rev. 2015; 95(2):405-511. 4. Baker PJ, et al. Androgen-mediated sex differences of cardiovascular responses in rats. The American journal of physiology. 1978; 235(2):H242-6. 5. Park KM, et al. Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. J Biol Chem. 2004;279(50):52282-92. 6. Bairey M., et al. "Sex and the kidneys: current understanding and research opportunities." Nature Reviews Nephrology (2019); 15.2:776-783. 7. Ma, H-Y., et al. "Estrogen and estrogen receptors in kidney diseases." Renal Failure (2021); 43.1: 619-642. 8. Conte, C. et al. "Role of Sex Hormones in Prevalent Kidney Diseases." International Journal of Molecular Sciences (2023); 24.9:8244. 9. Monteiro L.M. et al. Sex modifies the renal consequences of high fructose consumption introduced after weaning. Front. Physiol. (2023); 14:1090090. doi: 10.3389/fphys.2023.1090090. CAPES. This is the full abstract presented at the American Physiology Summit 2024 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.