Diet-induced obesity impairs salt-dependent downregulation of NCC activity.

Obesity is associated with increased salt sensitivity and hypertension, but the mechanisms underlying altered renal sodium handling remain unclear. The Na-Cl cotransporter (NCC) is a key regulator of sodium reabsorption in the distal convoluted tubule and is dynamically regulated in response to changes in electrolyte balance. This study investigated whether diet-induced obesity (DIO) alters NCC responsiveness to salt loading in vivo and explored the underlying mechanisms using an ex vivo kidney slice model. Male C57BL/6 J mice were fed either a control or a high-fat (HF) diet for 22 weeks, followed by 2 weeks of NaCl loading. HF-fed mice developed obesity, hyperglycemia, hyperinsulinemia, and elevated systolic blood pressure. Although NaCl loading increased urinary sodium excretion and decreased serum aldosterone in both control and obese mice, the increase in urinary sodium excretion was attenuated in obese mice, suggesting enhanced renal sodium reabsorption. In addition, NaCl loading reduced NCC phosphorylation in control mice, whereas this response was attenuated in DIO mice, with no change in total NCC expression. Notably, STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) phosphorylation was not significantly different among groups. In ex vivo kidney slice experiments, high-concentration insulin attenuated the high-potassium-induced suppression of NCC phosphorylation, whereas high glucose had no effect. These findings suggest that DIO impairs the normal suppression of NCC activity in response to salt loading without affecting basal NCC expression. Ex vivo findings suggest that insulin may modulate NCC responsiveness, although whether this mechanism contributes to NCC regulation in vivo remains uncertain. Impaired NCC responsiveness may promote renal sodium retention and could represent one potential mechanism linking obesity to altered sodium handling and blood pressure regulation.