Renal NHE3 is required to limit hypokalemia and metabolic acidosis during dietary potassium deficiency.

The sodium-hydrogen exchanger isoform 3 (NHE3) is a critical mediator of proximal tubule and thick ascending limb Na+ reabsorption and H+/NH4+ secretion, yet the physiological implications of its upregulation during low K+ intake remain poorly understood. We hypothesized that renal NHE3 is important for the acid-base response during K+ depletion. To test this, we utilized kidney-specific NHE3 knockout (NHE3KS-KO) mice. Following 10 days of a K+-deficient diet (< 30 ppm), NHE3KS-KO mice exhibited exacerbated hypokalemia compared to control mice, despite near complete elimination of urinary K+ excretion and comparable levels of ROMK and BKα protein abundance in both genotypes. Control and NHE3KS-KO mice developed hypernatremia secondary to a urinary concentrating defect; however, this was associated with a ~ 2-fold greater fluid intake in NHE3KS-KO mice. These effects occurred without changes in glomerular filtration rate. Both genotypes developed metabolic acidosis, which was significantly more severe in NHE3KS-KO mice. This exacerbated acidosis correlated with a ~ 60% lower mRNA expression of glutamine synthetase and a lower urinary NH4+/creatinine ratio. Furthermore, early histopathological signs of hypokalemic nephropathy were observed exclusively in some of the NHE3KS-KO mice. Our findings demonstrate that renal NHE3 attenuates the severity of hypokalemia and metabolic acidosis during K+ restriction, possibly via NH4+ formation/transport, which might accelerate the development of hypokalemic nephropathy.