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

Abstract

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.