Impaired distal renal potassium handling in streptozotocin-induced diabetic mice.

Diabetes is closely associated with K ⁺ disturbances during disease progression and treatment. However, it remains unclear whether K ⁺ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K ⁺ intake on systemic K ⁺ balance and renal K ⁺ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K ⁺ diet for 7 days to investigate the role of dietary K ⁺ intake in renal K ⁺ excretion and K ⁺ homeostasis and to explore the underlying mechanism by evaluating K ⁺ secretion-related transport proteins in distal nephrons. K ⁺ -deficient diet caused excessive urinary K ⁺ loss, decreased daily K ⁺ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K ⁺ balance and elevated plasma K ⁺ level under K ⁺ -loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na ⁺ channel (ENaC), and renal outer medullary K ⁺ channel (ROMK) was observed in diabetic mice fed either low or high K ⁺ diet. Moreover, amiloride treatment reduced urinary K ⁺ excretion and corrected hypokalemia in K ⁺ -restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K ⁺ excretion and normalized plasma K ⁺ levels in K ⁺ -supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K ⁺ balance and impaired renal K ⁺ handling under either low or high K ⁺ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K ⁺ excretion pathway, despite the possible role of NCC. NEW & NOTEWORTHY Neither low dietary K ⁺ intake nor high dietary K ⁺ intake effectively modulates renal K ⁺ excretion and K ⁺ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K ⁺ excretion and reduces plasma K ⁺ level in STZ mice under high dietary K ⁺ intake, an effect that may be partly due to the upregulation of ENaC activity.