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The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a−/−, proximal tubule (PT)-specific PT-Agtr1a−/− or PT-Nhe3−/− mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a−/− mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a−/− mice or NHE3 in PT-Nhe3−/− mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension. [ABSTRACT FROM AUTHOR]

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid–base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension. [ABSTRACT FROM AUTHOR]

In the present study, we tested the hypothesis that there are significant sex differences in angiotensin II (Ang II)-induced hypertension and kidney injury using male and female wildtype (WT) and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-). Twelve groups (n=8-12 per group) of adult male and female WT and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic minipump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in the proximal tubules versus systemic tissues. Basal systolic, diastolic, and mean arterial pressure were approximately 13+- 3 mmHg lower (P<0.01), while basal 24-h urinary Na+, K+, and Cl- excretion were significantly higher in both male and female PT-Agtr1a-/- mice than WT controls (P<0.01) without significant sex differences between different strains. Both male and female WT and PT-Agtr1a-/- mice developed hypertension (P<0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female WT and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in both male and female PT-Agtr1a-/- mice (P<0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in both male and female WT and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P<0.01). In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without revealing significant sex differences. [ABSTRACT FROM AUTHOR]

R4637 --> 715.19 --> It was previously reported the activation of the renin‐angiotensin system (RAS) in the clipped kidney plays a critical role in the development of two‐kidney, one‐clip Goldblatt hypertension (2K1C). However, most of previous studies used the global angiotensin II (Ang II) type 1a (AT1a) receptor (Agtr1a‐/‐) knockout model or used systemic AT1receptor blockers (ARB) to determine renal mechanisms of 2K1C hypertension. The roles of intratubular AT1 (AT1a) receptors or its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of 2K1C hypertension has not been determined previously. In the present study, we tested the hypothesis that genetic deletion of AT1 (AT1a) receptors selectively in the proximal tubules attenuates the development of 2K1C hypertension via AT1 (AT1a) receptor‐mediated, Na+/H+ exchanger 3 (NHE3)‐dependent mechanisms. To test the hypothesis, 2K1C Goldblatt hypertension was induced by placing a silver clip, 0.12 mm internal diameter, on the left renal artery for 4 weeks in adult male wild‐type (WT), global Agtr1a‐/‐, proximal tubule (PT)‐specific PT‐Agtr1a‐/‐, or PT‐Nhe3‐/‐ (Na+/H+ exchanger 3) mice, respectively. As expected, systolic blood pressure increased in a time‐dependent manner in wild‐type mice, reaching a maximal response by Week 3 (Basal: 112 ± 2 vs. 2K1C: 149 ± 4 mmHg, n=12, P<0.01). 2K1C hypertension in WT mice was associated with increases in renin mRNA expression in the clipped kidney (Control: 2066 ± 255 vs. Clipped: 3144 ± 569 copies/ng RNA, P<0.01), and decreases in renin mRNA expression in the nonclipped right kidney (1738 ± 341 copies/ng RNA, P<0.05). Plasma Ang II levels were significantly increased in WT mice with 2K1C hypertension (Control: 50.2 ± 7.2 vs. 2K1C: 109.7 ± 17.2 pg/ml, P<0.05). Glomerular and tubulointerstitial fibrotic responses were also significantly increased in the clipped kidney (P<0.01). By comparisons, the development of 2K1C hypertension was entirely prevented in Agtr1a‐/‐ (Basal: 88 ± 4 vs. 2K1C: 92 ± 2 mmHg, n=9, n.s.), or significantly attenuated in PT‐Agtr1a‐/‐ mice (Basal: 101 ± 2 vs. 2K1C: 104 ± 4 mmHg, n=12, n.s.) or in PT‐Nhe3‐/‐ mice (Basal: 103 ± 3 vs. 109 ± 5 mmHg, n.s.). Renin mRNA expression was not different in clipped and nonclipped kidney of Agtr1a‐/‐ mice, but it was decreased in the nonclipped kidney of PT‐Agtr1a‐/‐ mice (P<0.05). Furthermore, glomerular and tubulointerstitial fibrotic responses were also markedly attenuated in the clipped kidney in PT‐Agtr1a‐/‐ mice (P<0.05). We conclude that the results of the present study provide strong evidence for a critical role of AT1a receptors and NHE3 in the proximal tubules of the kidney in the development of 2K1C Goldblatt hypertension in mice. [ABSTRACT FROM AUTHOR]

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension. [ABSTRACT FROM AUTHOR]

R2851 --> The intratubular renin‐angiotensin system (RAS) via the angiotensinogen/renin/ACE/Ang II/AT1 (AT1a) receptor signaling pathways in the proximal tubules of the kidney play a critical role in the physiological regulation of blood pressure and the development of hypertension. Whether intratubular RAS continues to exert significant impacts on blood pressure and glomerular filtration responses to Ang II remains unknown. In the present study, we tested the hypothesis that deletion of AT1a receptors selectively in the proximal tubules of the kidney attenuates Ang II‐induced hypertensive and glomerular filtration responses (GFR) in aging PT‐Agtr1a‐/‐ mice. To test the hypothesis, 6 groups (n=8‐12 per group) of 20‐ to 24‐month‐old male wild‐type (WT) and PT‐Agtr1a‐/‐ mice were infused with or without a slow pressor dose of Ang II (~0.65 mg/kg/day, i.p.), supplemented with a 2% Na+ diet for 2 weeks. Systolic blood pressure was determined by telemetry and tail‐cuff techniques, whereas GFR was measured by the transdermal GFR monitoring technique with FITC‐sinistrin, and the pressure‐natriuresis responses was determined before and during Ang II infusion, respectively. Basal systolic blood pressure remained significantly lower in aging PT‐Agtr1a‐/‐ (104 ± 4 mmHg) than in aging WT mice (120 ± 4 mmHg, P<0.01), whereas basal GFR was significantly higher in aging PT‐Agtr1a‐/‐ mice (196.4 ± 14.7 µl/min) than in aging WT mice (142.6 ± 11.6 µl/min, P<0.01). Furthermore, the pressure‐natriuresis response was significantly augmented in aging PT‐Agtr1a‐/‐mice (P<0.05). Ang II infusion significantly induced hypertension (152 ± 3 mmHg, P<0.01) and decreased GFR in aging WT mice (122.4 ± 3.3 µl/min, P<0.01), as expected, but the hypertensive (135 ± 3 mmHg, P<0.01) and GFR responses were significantly improved in aging PT‐Agtr1a‐/‐mice (155.9 ± 10.1 µl/min, P<0.01), respectively. Finally, proximal tubule‐specific deletion of AT1a receptors significantly augmented the pressure‐natriuresis response and natriuretic responses to Ang II infusion in aging PT‐Agtr1a‐/‐mice (P<0.01). Taken together, the results of the present study suggest that intratubular Ang II and AT1a receptors in the proximal tubules continue to play a key role in the development of Ang II‐induced hypertension in aging WT mice and that deletion of AT1a receptors selectively in the proximal tubules attenuates Ang II‐induced hypertension and improves glomerular filtration in aging PT‐Agtr1a‐/‐ mice. [ABSTRACT FROM AUTHOR]

The sodium (Na + )/hydrogen (H + ) exchanger 3 (NHE3) is one of the most important Na + /H + antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid-base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na + and the extrusion of intracellular H + from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na + from small and large intestines and reabsorbing >50% of filtered Na + in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na + transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nwia, Li, Leite, Hassan and Zhuo.)