scholarly journals PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES ANGIOTENSIN II-INDUCED HYPERTENSION BY INCREASING GLOMERULAR FILTRATION AND THE PRESSURE-NATRIURESIS RESPONSE

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e64-e65
Author(s):  
Xiao Li ◽  
Ana Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Jia Zhuo
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Glomerular Filtration ◽  
Induced Hypertension ◽  
Pressure Natriuresis ◽  
Specific Deletion

Abstract P041: Proximal Tubule-specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Lowers Basal Blood Pressure And Attenuates Angiotensin Ii-induced Hypertension By Increasing Glomerular Filtration And The Pressure-natriuresis Response

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Ana P Leite ◽  
Liang Zhang ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Pressor Response ◽  
Control Group ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Basal Blood Pressure ◽  
Pressure Natriuresis ◽  
Specific Deletion

The present study tested the hypothesis that intratubular angiotensin II (Ang II) and AT 1a receptors in the proximal tubules of the kidney plays an important role in basal blood pressure control and in the development of Ang II-induced hypertension. Mutant mice with proximal tubule-specific deletion of AT 1a receptors in the kidney, PT- Agtr1a -/- , were generated to test the hypothesis. Eight groups (n=7-12 per group) of adult male wild-type (WT) and PT- Agtr1a -/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg, i.p.). Basal systolic, diastolic, and mean arterial pressures were ~13 ± 3 mmHg lower in PT- Agtr1a -/- than WT mice ( P <0.01). Basal glomerular filtration rate (GFR), as measured using transdermal FITC-sinistrin, was significantly higher in PT- Agtr1a -/- mice (WT: 160.4 ± 7.0 μl/min vs. PT- Agtr1a -/- : 186.0 ± 6.0 μl/min, P <0.05). Basal 24 h urinary Na + excretion (U Na V) was significantly higher in PT- Agtr1a -/- than WT mice ( P <0.01). In response to Ang II infusion, both WT and PT- Agtr1a -/- mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P <0.01) and PT- Agtr1a -/- mice (Δ39 ± 5 mmHg, P <0.01). However, the absolute blood pressure level was still 16 ± 3 mmHg lower in PT- Agtr1a -/- mice ( P <0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice ( P <0.01), and to 129.4 ± 18.6 μl/min in PT- Agtr1a -/- mice ( P <0.01), respectively. In WT mice, U Na V increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group ( P <0.01). In PT- Agtr1a -/- mice, U Na V increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group ( P <0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT- Agtr1a -/- mice ( P <0.01). Finally, proximal tubule-specific deletion of AT 1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion ( P <0.01) or a 2% high salt diet ( P <0.01). We concluded that deletion of AT 1a receptors selectively in the proximal tubules lowers basal blood pressure and attenuates Ang II-induced hypertension by increasing GFR and promoting the natriuretic response in PT- Agtr1a -/- mice.

Abstract 077: Proximal Tubule-Specific Deletion of the NHE3 (na + /h + Exchanger 3) in the Kidney Attenuates Angiotensin II-Induced Hypertension in Mice

Hypertension ◽  
2019 ◽  
Vol 74 (Suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Dongmin Zhu ◽  
Xu Chen ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Induced Hypertension ◽  
Specific Deletion

scholarly journals PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES CIRCULATING AND INTRATUBULAR ANGIOTENSIN II-INDUCED HYPERTENSION IN MICE

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e7
Author(s):  
Xiao Li ◽  
Ana Paulo Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Liang Zhang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Induced Hypertension ◽  
Specific Deletion

scholarly journals Proximal Tubule-Specific Deletion of the NHE3 (Na + /H + Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice

Hypertension ◽  
2019 ◽  
Vol 74 (3) ◽  
pp. 526-535 ◽  
Author(s):  
Xiao C. Li ◽  
Dongmin Zhu ◽  
Xu Chen ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Specific Deletion

A18558 Proximal tubule-specific deletion of AT1a receptors in the kidney attenuates angiotensin II-induced hypertension

2018 ◽  
Vol 36 ◽  
pp. e92
Author(s):  
Xiaowen Zheng ◽  
Xiao Chun Li ◽  
Jianfeng Zhang ◽  
Xu Chen ◽  
Dongmin Zhu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Induced Hypertension ◽  
Specific Deletion

Abstract 023: Collecting Duct (Pro)Renin Receptor Mediates Angiotensin II-induced Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Fei Wang ◽  
Kexin Peng ◽  
Xiaohan Lu ◽  
Kevin Yang ◽  
Mi Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Direct Action ◽  
Collecting Duct ◽  
Second Phase ◽  
Na Transport ◽  
Dual Effect ◽  
Induced Hypertension ◽  
Nanomolar Range ◽  
Local Generation ◽  
Specific Deletion

Within the kidney, (pro)renin receptor (PRR) is predominantly expressed in the intercalated cells (IC) of collecting duct (CD) where its expression is induced by angiotensin II (AngII). Here we examined the function of PRR in the CD by analyzing mice with CD-specific deletion of PRR (CD PRR KO) using AQP2-Cre which has recently been shown to target both IC and principal cells (PC). Radiotelemetry demonstrated that the null mice were largely resistant to AngII-induced hypertension (MAP on day 7: Floxed/AngII 137.4 ± 3.5 vs. KO/AngII 121.2 ± 1.1 mmHg, p<0.05, n=4), accompanied with reduced urinary soluble PRR (sPRR) and aldosterone levels. Electrophysiology analysis demonstrated that within minutes activation of PRR by 10 nM prorenin induced a transient increase in amiloride-sensitive Na+ transport in cultured mpkCCD cells (Ieq: 1.85 ± 0.17 vs. 1.30 ± 0.06 μA/cm2, p<0.05). Interestingly, this was followed by a second phase of ENaC activation after 6 h, which reached the plateau activation at 24 h, accompanied with increased aldosterone release as assessed by ELISA (14.41 ± 0.92 vs. 5.45 ± 0.28 pg/ ml/μg protein, p<0.05). The chronic but not acute phase of ENaC activation was abolished by eplerenone. Both phases of ENaC activation depended on Nox4-derived reactive oxygen species (ROS). Immunostaining using an antibody against sPRR (the N terminus) showed exclusive labeling in the principle cells (PC) whereas the labeling with the C-terminal antibody was exclusively found in IC. A recombinant histidine-tagged sPRR, termed sPRR-His, in the nanomolar range induced a similar dual effect on ENaC activation as prorenin. Intravenous infusion of sPRR-His in CD PRR KO mice for 5 days completely restored the hypertensive response to AngII (MAP: 135.5 ± 7.5 vs. 116.7 ± 5.7 mmHg, p<0.05). We conclude that: 1) CD PRR mediates AngII-induced hypertension; 2) PRR activation in the CD leads to increased ENaC activity acutely through the direct action of ROS and chronically through local generation of aldosterone; 3) sPRR derived from IC may act in a paracrine fashion to stimulate Na+ transport in PC.

scholarly journals Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Xiao Chun Li ◽  
Ana Paula Oliveira Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Xu Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Normal Blood ◽  
Ang Ii ◽  
Normal Blood Pressure ◽  
Wild Type ◽  
Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

Abstract P646: Vascular AT1 Angiotensin Receptors Regulate Sodium Transporter Abundance in Kidney Epithelium

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Matthew A Sparks ◽  
Donna L Ralph ◽  
Daian Chen ◽  
Hooman A Azad ◽  
Susan B Gurley ◽  
...  
Keyword(s):  
Angiotensin Receptors ◽  
Loop Of Henle ◽  
Ang Ii ◽  
At1 Receptors ◽  
Renal Vasoconstriction ◽  
Lower Baseline ◽  
Induced Hypertension ◽  
Sodium Transporter ◽  
Pressure Natriuresis ◽  
Specific Deletion

Vasoconstriction is a signature physiological action of angiotensin II (AngII) acting via AT1 receptors (AT1R). In order to define the contribution of AT1R in vascular smooth muscle cells (VSMCs) to BP control, we generated mice with cell-specific deletion of AT1AR from VSMCs (SMKOs) using Cre-loxp technology. Baseline BP was reduced by ~7 mmHg and responses to AngII-induced hypertension were significantly blunted by in SMKO mice compared to controls (16 vs. 30 mm Hg change in BP from baseline after 4 wks AngII, P<0.02). Baseline renal blood flow (RBF) was higher, and renal vasoconstriction after Ang II was impaired in SMKOs. Moreover, SMKO mice displayed Na+ sensitivity and exaggerated natriuresis during chronic AngII infusion. To investigate the mechanism of the lower baseline BP and the enhanced natriuresis during AngII infusion (1000ng/kg/min for 5 days), we measured a panel of key Na+ transporters in the kidney by immunoblot. Baseline measurements in SMKO vs. controls detected reductions in NKCC2 in both cortex (0.8±0.03 vs. 1±0.03; P=0.0002) and medulla (0.6±0.02 vs. 1±0.05; P<0.0001); medullary NHE3 was similarly reduced (0.6±0.07 vs. 1±0.07; P=0.002). In controls, AngII infusion was associated with reduced levels of cortical and medullary NHE3 and medullary NKCC, consistent with the pressure-natriuresis response, whereas cortical NKCC, NCC and ENaC were all significantly activated. By contrast, in SMKOs, there was no AngII infusion dependent depression in cortical or medullary NHE3, nor medullary NKCC. However, the extent of increase in activated (cleaved) αENaC was significantly less than controls (cortex: 1.46±0.16 vs. 2.58±0.17, P=0.002; medulla: 1.49±0.09 vs. 2.22±0.31, P=0.01). Yet, 24 hr urinary aldosterone excretion was not different between the groups (18.6±2.7 vs. 15.8±4.5 ng/24hrs). Our studies indicate that the lower baseline BP in SMKO mice is associated with reduced Na+ transporter abundance along the loop of Henle, and that attenuated hypertension and improved natriuresis during AngII infusion are associated with diminished ENaC activation. In conclusion, we suggest that vascular-epithelial cross-talk modulates renal Na+ handling and thereby contributes to control of BP at baseline and during hypertension.

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