Plasma potassium plays a major role in controlling the concentrating ability of the kidney

Abstract

Hypokalemia can induce diabetes insipidus (DI), characterized by loss of free‐water reabsorption, loss of urine concentrating ability, polyuria and polydipsia. Although the disorder has been described for decades, the pathophysiological mechanisms remain poorly understood. In addition, it still unclear if there is a sexual dimorphism. In this study, we characterized hypokalemia‐induced DI over a spectrum of plasma potassium levels in mice fed a range of low potassium diets (LKD) between 0% and 0.11% K+, over 8 days compared to control diet (1%K+). We observed that 0%K+ and 0.026%K+ diets both induced hypokalemia, polyuria and a decrease in urine osmolality starting after 5 and 6 days, respectively. However, the 0.056%K diet induced only mild DI starting at day 7. Interestingly, the 0.11%K diet did not result in DI. We then assessed the DI in males and females mice fed with LKD (0%K+) or control diet for 8 days. After 3 days of LKD, both males and females exhibited decrease in urine osmolality which was more sever in females (−21%) than in males (−12%). Profound diuresis was observed at day 5 and it was more enhanced in females (5.2 +/−0.58 mL/day) than in males (3.0 +/−0.43 mL/day), which might be a consequence of the more severe hypokalemia in females compared to males (2.6 +/−0.29 versus 3.5 +/−0.08 mmol/L) after 8 days of LKD. Moreover, it has been shown that the urinary concentration defect occurs mainly in the inner medullary collecting duct (IMCD), involving a reduction in AQP2 channel expression. Recent studies localized AQP2 protein in the autophagosome in the IMCD of DI models suggesting the autophagic degradation of AQP2 under hypokalemia‐induced DI (Khositseth S., Sci rep 2015)(Kim WY., Sci rep 2019). We confirmed and extended this observation, finding that after 8 days of LKD, the ATG12‐Atg5‐Atg16 complex, the LC3II/LC3I ratio, and P62 were all increased in the medulla but no difference was detected by western blot in the cortex. However, we observed that AQP2 levels were more severely decreased in the cortex than in the medulla of the hypokalemic versus control mice suggesting that pathways other than autophagy are at play. Together, the data indicate: i) a tight relationship between loss of the renal concentrating ability and development of hypokalemia, ii) hypokalemia in response to dietary potassium deficiency is more sever in female mice than males, and as a consequence, females are more prone to develop DI than males, iii) the autophagy is induced in the medulla of the hypokalemic mice, iv) The hypokalemia‐induced decrease in AQP2 is correlated with induction of autophagy in the medulla but not in the cortex. Support or Funding Information NIH