Circulating levels of tissue inhibitor of metalloproteinase-3, a protein with anti-angiogenic and pro-hypertensive effects, are increased in preeclampsia

hydrogen (H + ) exchanger 3 (NHE3), alone in the proximal tubules (PT) of the kidney lowered basal blood pressure and attenuated Ang II-induced hypertension.As NHE3 is well-recognized as the downstream target of AT 1 (AT 1a ) receptor-mediated, Ang II-stimulated proximal Na + transport, it is not known whether basal blood pressure and Ang II-induced hypertension would be further attenuated in mutant mice with double knockout of AT 1a receptors and NHE3 in the proximal tubules.Methods Used: In the present study, we generated proximal tubule-specific AT 1a receptor and NHE3 double knockout mice, PT-Agtr1a -/-/Nhe3 -/-mice, using the iL-Sglt2-Cre/LoxP approach.Adult male wild-type (WT), PT-Agtr1a -/-, PT-Nhe3 -/-, and PT-Agtr1a -/-/Nhe3 -/- double knockout mice were treated with vehicle (or sham as time-controls), a slow pressor dose of Ang II infusion for 2 weeks (500 µg/kg body wt./day, i.p.), or induction of two-kidney, one-clip (2K1C) Goldblatt hypertension by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks, respectively.Summary of Results: In WT mice, basal systolic blood pressure was 118 ± 3 mmHg (n = 9), which increased to ∼143 ± 5 mmHg in response to Ang II infusion (P < 0.01, n = 10) or to induction of 2K1C Goldblatt hypertension (n = 12, P < 0.01), respectively.By comparison, basal systolic blood pressure was 15 ± 2 mmHg lower in agematched PT-Agtr1a -/-mice (P < 0.01), or 13 ± 3 mmHg lower in PT-Nhe3 -/-mice than WT mice (P < 0.01).Double deletion of AT 1a receptors and NHE3 selectively in the proximal tubules further but only moderately decreased basal blood pressure to 98 ± 2 mmHg in PT-Agtr1a -/ -/Nhe3 -/-double knockout mice (P < 0.05, n = 10).In response to Ang II infusion, systolic blood pressure increased only to ∼126 ± 3 mmHg in PT-Agtr1a -/-or PT-Nhe3 -/-mice (P < 0.01).Interestingly, 2K1C Goldblatt hypertension was markedly attenuated in PT-Agtr1a -/- (108 ± 3 mmHg, P < 0.01, n = 10), PT-Nhe3 -/-(110 ± 2 mmHg, P < 0.01, n = 10), or PT-Agtr1a -/-/Nhe3 -/-double knockout mice (103 ± 2 mmHg, P < 0.01, n = 8), respectively.Glomerular filtration rate in PT-Agtr1a -/-/Nhe3 -/- mice, as estimated by the fluorescein-labeled sinistrin technique, was significantly lower than PT-Agtr1a -/-mice (P < 0.05), whereas urinary Na + excretion was higher than WT mice, but comparable to PT-Agtr1a -/-or PT-Nhe3 -/- mice due to inhibition of proximal tubule Na + reabsorption.Conclusions: We conclude that the present study strongly support the hypothesis that the intratubular Ang II/AT 1a receptor/NHE3 signaling plays a key role in maintaining basal blood pressure homeostasis and the full development of Ang II-induced or 2K1C Goldblatt hypertension.