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1 Departments of Molecular and Cellular Physiology, and 2 Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and 3 Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109
The Na/H exchanger isoform 3 (NHE3) is expressed in the proximal
tubule and thick ascending limb and contributes to the reabsorption of
fluid and electrolytes in these segments. The contribution of NHE3 to
fluid reabsorption was assessed by micropuncture in homozygous
(Nhe3
/)
and heterozygous
(Nhe3+/)
knockout mice, and in their wild-type (WT,
Nhe3+/+)
littermates. Arterial pressure was lower in the
Nhe3/
mice (89 ± 6 mmHg) compared with
Nhe3+/+ (118 ± 4) and
Nhe3+/
(108 ± 5). Collections from proximal and distal tubules
demonstrated that proximal fluid reabsorption was blunted in both
Nhe3+/ and
Nhe3/
mice (WT, 4.2 ± 0.3;
Nhe3+/,
3.4 ± 0.2; and
Nhe3/,
2.6 ± 0.3 nl/min; P < 0.05).
However, distal delivery of fluid was not different among the three
groups of mice (WT, 3.3 ± 0.4 nl/min;
Nhe3+/,
3.3 ± 0.2 nl/min; and
Nhe3/,
3.0 ± 0.4 nl/min; P < 0.05). In
Nhe3/
mice, this compensation was largely attributable to decreased single-nephron glomerular filtration rate (SNGFR): 10.7 ± 0.9 nl/min in the
Nhe3+/+ vs. 6.6 ± 0.8 nl/min in the
Nhe3/,
measured distally. Proximal-distal SNGFR differences in
Nhe3/
mice indicated that much of the decrease in SNGFR was due to activation
of tubuloglomerular feedback (TGF), and measurements of stop-flow
pressure confirmed that TGF is intact in
Nhe3/
animals. In contrast to
Nhe3/
mice, normalization of early distal flow rate in
Nhe3+/
mice was not related to decreased SNGFR (9.9 ± 0.7 nl/min), but rather, to increased fluid reabsorption in the loop segment
(Nhe3+/+, 2.6 ± 0.2;
Nhe3+/,
3.6 ± 0.5 nl/min). We conclude that NHE3 is a major Na/H exchanger isoform mediating Na+ and fluid
reabsorption in the proximal tubule. In animals with NHE3 deficiency,
normalization of fluid delivery to the distal tubule is achieved
through alterations in filtration rate and/or downstream transport processes.
kidney; single-nephron glomerular filtration rate; sodium/proton exchange; proximal tubule; tubuloglomerular feedback
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