Female Age and Prior Pregnancies Are Associated With Increased Propensity for Sodium Retention in Rats

Rodent models are indispensable when investigating renal handling of water and electrolytes in both health and disease. Most experiments induce disease states on healthy young animals, but these do not necessarily recapitulate renal function following aging or prior female reproduction. Thus, the physiological interpretation and translational potential may be partially limited. In a recent publication in Acta Physiologica entitled “Age-related Adaptations in Renal Tubular Function in Female Rats” 1, Edwards and colleagues take an important leap forward by investigating the impact of age and past pregnancies on renal function by systematically comparing 12-month-old female breeder rats (corresponding to mid-life with reproductive history) to 4.5-month-old adolescent virgin females. Interestingly, in the 12-month-old breeder rats, the authors observed a tendency to higher glomerular filtration rate (GFR) of ~25% (p = 0.10), similar urinary excretion of Na+ and K+ and an increased response to the diuretic hydrochlorothiazide (HCTZ). The response to a K+ rich meal was unchanged. Of note, overall aquaporin-2 (AQP2) abundance in the collecting duct principal cells was unaltered, but AQP2 phosphorylation on serine 256 (pS256-AQP2) was increased by ~50% which may indicate increased collecting duct water permeability (Figure 1). In the kidneys, GFR largely determines the downstream need for tubular reabsorption of sodium and water. Renal sodium handling is mediated by different Na+ transporters, with most of the sodium handling occurring in the proximal tubule and thick ascending limb of Henle, with subsequent reabsorption in the distal tubule and fine-tuning in the collecting duct 2. Water reabsorption is mediated via aquaporins, with constitutive water reabsorption in the proximal tubule and subsequent hormone-regulated fine-tuning in the collecting duct 3, 4. Adaptive changes in renal expression and/or localization of several of these Na+ transporters and aquaporins are hormonally mediated in relation to changes in GFR as well as altered sodium and water intake. Edwards and colleagues 1 show that GFR was not significantly different between 4.5-month adolescent virgin female rats and 12-month mid-life female breeder rats where a tendency to higher GFR was observed. A systematic review by Guppy and colleagues from 2024 5 found an annual decline rate of GFR in human adults without hypertension of −0.37 to −1.07 mL/min/1.73 m2/year. Similarly, age-related decline in GFR in male rats was reported by Reckelhoff and colleagues in 1992 comparing old male rats aged 20–22 months vs. adolescent male rats aged 4–5 months (0.67 ± 0.05 mL/min/g KW vs. 1.00 ± 0.08 mL/min/g KW, p < 0.02) when adjusted for kidney weight 6. Thus, the study by Edwards and colleagues 1 indicates that age-related changes in GFR are not uniform but depend on physiological contexts such as age (mid-life vs. old age), gender and for females, perhaps reproductive history. Compared to adolescent rats, adult female breeder rats had increased propensity for Na+ retention and an increased response to the diuretic hydrochlorothiazide-HCTZ. They had decreased relative abundance of several Na+ transporters but when adjusted for the larger kidney weight in 12-month-old rats, the overall abundance was equal. Overall abundance of AQP2 did not change but the elevated pS256-AQP2 indicates adaptive increased collecting duct water permeability compared to the 4.5-month-old rats. Thus, these adjustments may contribute to maintaining Na+ and fluid balance in response to renal changes due to age and prior reproduction in the 12-month-old female breeder rats. Whether the preservation of the overall abundance of transport proteins reflects altered distribution due to inferred structural nephron remodeling with increased kidney size or, more simply, changes in circulating angiotensin or aldosterone, remains to be determined. It is well known that kidney function gradually declines with age while chronic diseases and hypertension become more prevalent in middle age. Despite this, rodent models are frequently based on healthy young animals. This includes models of chronic kidney disease (CKD) such as unilateral ureteral obstruction, where up to 2 weeks of obstruction results in significant renal changes including fibrosis and tubular atrophy 7. While the models are powerful to dissect the changes occurring in CKD, challenges when testing intervention therapies to reverse or halt renal deterioration occurring in CKD may arise. More than 90% of drugs fail in clinical trials overall 8. The reasons are multifaceted where contributing factors could be limitations in translational models that bridge rodent and human physiology but also that the reference starting point in animal experiments is often healthy young animals, which may misrepresent patient physiology—especially in females in mid-life with a reproductive history. In conclusion, the study by Edwards and colleagues 1 suggests that the kidneys adapt to age and prior female reproduction with altered Na+ handling. Future studies will clarify the regulatory mechanisms underlying these adaptations. Therefore, to improve translational potential when studying hypertension and renal diseases, it is essential to carefully consider age and female reproductive history when choosing animal models. Text editing: ChatGPT (OpenAI) was used for language editing of selected sentences. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.