Kidney Week

Abstract: SA-PO768

Deletion of AT1a Receptors Selectively in the Proximal Tubules of the Kidney Augments Glomerular Filtration in Male and Female PT-Agtr1a-/- Mice

Session Information

• Hypertension and CVD: Mechanisms
  November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1503 Hypertension and CVD: Mechanisms

Authors

• Li, Xiao C., Tulane University School of Medicine, New Orleans, Louisiana, United States

Xiao C. Li,

• Zhuo, Jia L., Tulane University School of Medicine, New Orleans, Louisiana, United States

Jia L. Zhuo,

Background

It is well recognized that circulating angiotensin II (Ang II) plays a key role in the regulation of glomerular filtration via activation of AT₁ (AT_1a) receptors. However, whether Ang II and AT₁ (AT_1a) receptors in the proximal tubules play an important role in the regulation of glomerular filtration remains unknown.

Methods

We tested the hypothesis that deletion of AT_1a receptors selectively in the proximal tubules augments glomerular filtration in male and female PT-Agtr1a^-/- mice. PT-Agtr1a^-/- mice were generated using the iL-Sglt2-Cre/Agtr1a-floxed approach. Two groups of adult male and female wild-type (WT) and PT-Agtr1a^-/- mice were infused with or without a slow pressor dose of Ang II for 2 weeks via an osmotic minipump (~500 µg/kg body wt./day, i.p.). Whole-kidney glomerular filtration rate (GFR) was determined using the transdermal GFR monitoring technique with FITC-sinistrin (MediBeacon, 10 mg/100 g body wt., i.v).

Results

In WT mice, basal systolic blood pressure was 116 ± 3 mmHg, which increased to 146 ± 5 mmHg in response to Ang II infusion (P<0.01). Basal GFR was 160.8 ± 14.4 µl/min in male (n=9) and 149.9 ± 18.4 µl/min in female mice (n.s., n=7). In response to Ang II infusion, GFR was significantly decreased by ~25% to a similar extent in male and female WT mice (P<0.01). By comparison, basal systolic blood pressure was 13 ± 2 mmHg lower in age-matched male (n=13) and female (n=10) PT-Agtr1a^-/- mice (P<0.01). In response to Ang II infusion, systolic blood pressure increased to 128 ± 3 mmHg in male and female PT-Agtr1a^-/- mice (P<0.01). Interestingly, basal GFR was ~20% higher in male (190.6 ± 11.0 µl/min, P<0.05, n=10) and ~30% higher in female PT-Agtr1a^-/- mice (203.8 ± 21.5 µl/min, P<0.05, n=9) than WT mice, respectively. In response to Ang II infusion, GFR was significantly decreased by ~25% in male PT-Agtr1a^-/- mice (155.9 ± 20.0 µl/min, P<0.01, n=10). However, Ang II infusion had no significant effect on GFR in female PT-Agtr1a^-/- mice (191.2 ± 18.8 µl/min, n.s., n=7).

Conclusion

Our findings suggest that deletion of AT_1a receptors selectively in the proximal tubules inhibits AT_1a receptor-mediated, Ang II-stimulated proximal tubule sodium reabsorption, which increases the end proximal tubule sodium delivery to the macula densa and impairs the tubuloglomerular feedback response in PT-Agtr1a^-/- mice.

Funding

• NIDDK Support