NHE3 in the thick ascending limb is required for sustained but not acute
furosemide-induced urinary acidification.
Authors Xue J, Thomas L, Dominguez Rieg JA, Fenton RA, Rieg T
Submitted By Submitted Externally on 6/13/2022
Status Published
Journal American journal of physiology. Renal physiology
Year 2022
Date Published 5/1/2022
Volume : Pages Not Specified : Not Specified
PubMed Reference 35635321
Abstract The Na+/H+ exchanger isoform 3 (NHE3) facilitates Na+ reabsorption and H+
secretion by the kidneys. Despite stronger NHE3 abundance in the thick ascending
limb (TAL) compared to the S1 and S2 segments of the proximal tubule, the role
of NHE3 in the TAL is poorly understood. To investigate the role of NHE3 in the
TAL, we generated and phenotyped TAL-specific NHE3 knockout mice (NHE3TAL-KO).
Compared to control mice, NHE3TAL-KO mice did not show significant differences
in body weight, blood pH or plasma Na+, K+ or Cl- levels. Fluid intake trended
to be higher and urine osmolality was significantly lower in NHE3TAL-KO mice.
Despite a similar GFR, NHE3TAL-KO mice had a greater urinary K+/creatinine
ratio. One proposed role of NHE3 relates to furosemide-induced urinary
acidification. Acute bolus treatment with furosemide under anesthesia did not
result in differences in the dose dependence of urinary flow rate, Cl- excretion
or maximal urinary acidification between genotypes; however, in contrast to
control mice, urinary pH returned immediately towards baseline levels in
NHE3TAL-KO mice. Chronic furosemide treatment reduced urine osmolality similarly
in both genotypes but metabolic alkalosis, hypokalemia and calciuresis were
absent in NHE3TAL-KO mice. Compared to vehicle, chronic furosemide treatment in
control mice resulted in greater NKCC2 and lower Npt2a abundances, effects that
were absent in NHE3TAL-KO mice. In summary, NHE3 in the TAL plays a role for the
sustained acidification effect of furosemide. Consistent with this, long-term
treatment with furosemide did not result in metabolic alkalosis in NHE3TAL-KO