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 to 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), epithelia 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+ level 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.