ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

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
  • Zhuo, Jia L., Tulane University School of Medicine, New Orleans, Louisiana, United States
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 (AT1a) receptors. However, whether Ang II and AT1 (AT1a) 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 AT1a 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 AT1a receptors selectively in the proximal tubules inhibits AT1a 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