Influence of Murine Background Strain on Renal Water Balance and Urine Concentration

Background: Kidneys are essential in maintaining body fluid and electrolyte balance. Several mouse strains, specifically C57 and 129, are widely used for studying renal physiology and diseases. Previous observations suggest background strains influence urinary behaviors and diuretic responses in mice; however, a systematic analysis has not yet been performed and the underlying mechanisms for these differences remain unclear. Methods: The present study aims to examine differences in salt and water handling between the C57 and 129 mouse strains. Adult male mice were housed in metabolic cages for 24-hour urine collection. Weight, water, and food intake were measured daily. At the end of the study, mice were sacrificed for blood and tissue collections. Results: We show that while C57 mice demonstrate greater 24-hour water consumption and 24-hour urinary output, plasma osmolality and blood chemistry between strains remain comparable. Both strains demonstrate greatest urination during dark periods. Despite having a greater body weight, kidneys were significantly smaller in C57 male mice compared to 129s. Western blot reveals C57 mice have remarkably reduced expression of both the Na-K-Cl cotransporter (NKCC2) and renal outer medullary potassium channel (ROMK), suggesting reduced Na+ reabsorption in the thick ascending limb of C57 mice. Notably, the expression of the sodium-chloride transporter (NCC) remains consistent between the two strains. Additionally, C57 mice show significantly less expression of several aquaporins (AQPs), specifically AQP1, AQP2, and AQP3; indicating impaired water reabsorption along the nephron. Taken together, our data suggests differences in sodium and water handling, as a consequence of NKCC2 and AQPs expression, contribute to the discrepancies in water balance and urine concentrating abilities seen between C57 and 129 mice. Finally, both uromodulin expression and PKA-phosphorylated substrate abundance were appreciably lower in the C57 strain and as such, may contribute to the decreased expression of AQP2 and NKCC2 by means of the vasopressin-cAMP-PKA pathway. Conclusion: Our data emphasizes the idea that murine background strains are highly variable and should be considered in designing renal physiology studies. Funding: NIDDK Support