Premium
The Chronic Effect of Tubular pH on TGF
Author(s) -
Wei Jin,
Wang Shaohui,
Wang Lei,
Zhang Gensheng,
Zhang Jie,
Yip KayPong,
Liu Ruisheng
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.739.1
Subject(s) - macula densa , tubuloglomerular feedback , chemistry , medicine , endocrinology , nitric oxide , nos1 , excretion , nitric oxide synthase , renal function , renin–angiotensin system , blood pressure , biochemistry
Tubuloglomerular feedback (TGF) is an important mechanism for regulation of glomerular filtration rate (GFR), sodium excretion and blood pressure. Nitric oxide synthase 1 (NOS1) is the primary isoform of NOS expressed in the macula densa and the major splice variant is NOS1β. Nitric oxide (NO) generated by the macula densa blunts TGF response. Elevation of intracellular pH at macula densa activates NOS1 during TGF. However, whether chronic changes of renal pH have any effect on TGF response in vivo has not been clarified yet. We hypothesized in present study that elevation of renal pH inhibits TGF response by increasing NOS1β expression in the macula densa. C57BL/6J mice were divided into 3 groups treated with 0.5% NaCl, 0.72% NaHCO 3 (same mEq of Na + as in NaCl) or 0.46% NH 4 Cl (same mEq of Cl − as in NaCl), respectively, for two weeks. Urine pH was significantly increased to 7.8±0.5 in NaHCO 3 treated group and decreased to 6.8±0.3 in NH 4 Cl treated group, compared with the control NaCl group (7.3±0.3). TGF was assessed in vivo by measuring the change in proximal tubular stop flow pressure (ΔPsf) induced by an increase of perfusion rate in late proximal tubules from 0 to 40nl/min. TGF was significantly blunted to 4.2±0.5 mmHg in NaHCO 3 treated group but significantly enhanced to 7.4±1.1 mmHg in NH 4 Cl treated group, compared with the mice fed NaCl (6.0±0.7mmHg,). GFR in conscious mice were measured by plasma FITC‐inulin clearance after a single bolus injection of FITC‐inulin. There was no significantly difference among three groups, which was 237±13.7 μl/min in NaHCO 3 group, 219±17.2 μl/min in NH 4 Cl group and 241±12.8 μl/min in NaCl group. The expression of NOS1β in MD, measured by Western Blot was significantly increased with a more than 5 folds higher in NaHCO 3 treated group than that in NaCl treated group. On the contrary, NOS1β level was significantly decreased in NH 4 Cl group with about 1/3 value of that in NaCl group. To further determine the role of NOS1β in the alteration of TGF by renal pH, we repeated the experiments in MD specific NOS1 KO (MD‐NOS1‐KO) mice, which were developed by our laboratory. Although urine pH in the MD‐NOS1‐KO mice was similar to the wild type mice in 3 treated goups (7.9±0.8, 6.6±0.5, and 7.4±0.2), the difference in TGF among 3 groups were diminished. The TGF response was 7.5±0.7mmHg in NaHCO 3 group, 8.5±1.6 mmHg in NH 4 Cl group, and 7.9±1.2 mmHg in NaCl group. In conclusion, chronic elevation of tubular pH by NaHCO 3 treatment increases the expression of NOS1β in MD and blunts TGF; on the contrary, acid tubular solutes decrease the NOS1β level in the MD and enhance TGF. Therefore, NOS1β in MD modulated by renal pH by NaHCO 3 treatment or dietary acid‐base load could be a potential target for prevention and treatment for hypertension and chronic kidney disease.