Kidney Week

Abstract: SA-PO0941

Proximal Tubule-ACE2 Deletion Attenuates Acute Cardiorenal Syndrome-Induced Chronic GFR and Vascular Change in Male but Not Female Mice

Session Information

• Pathology: Updates and Insights
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1800 Pathology and Lab Medicine

Authors

• Aomura, Daiki, Oregon Health & Science University, Portland, Oregon, United States

Daiki Aomura, MD, PhD

• Burfeind, Kevin G., Oregon Health & Science University, Portland, Oregon, United States

Kevin G. Burfeind, MD, PhD

• Hebert, Jessica Faith, Oregon Health & Science University, Portland, Oregon, United States

Jessica Faith Hebert, PhD

• Funahashi, Yoshio, Nagoya Daigaku Igakubu Fuzoku Byoin, Nagoya, Aichi Prefecture, Japan

Yoshio Funahashi, MD, PhD

• Munhall, Adam C., Oregon Health & Science University, Portland, Oregon, United States

Adam C. Munhall

• Groat, Tahnee, Oregon Health & Science University, Portland, Oregon, United States

Tahnee Groat, MPH

• Gurley, Susan B., University of Southern California Keck School of Medicine, Los Angeles, California, United States

Susan B. Gurley, MD, PhD

• Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States

Michael Hutchens, MD, MA

Background

Acute heart failure causes AKI (cardiorenal syndrome type 1, CRS1) and may induce AKI-CKD transition. Angiotensin-converting enzyme 2 (ACE2) regulates blood pressure and is highly expressed in the proximal tubule (PT). The role of ACE2 in PT, in CRS1-induced CKD is unknown. We addressed this question using PT-specific ACE2 gene-deleted mice (PTACE2KO) in a translational model of CRS1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR).

Methods

Male and female PTACE2KO (Ace2^fl/fl;Pck1-Cre) and controls (Ace2^fl/fl) underwent CA/CPR or sham. CA was induced with potassium chloride; CPR, started after 8m CA, included chest compressions and epinephrine. Glomerular filtration rate (GFR, μL/min/100 g body weight) and the thickness of renal arcuate artery wall (TRAAW) were assessed on day 49 after CA/CPR or sham. GFR was measured by transcutaneous disappearance of FITC-sinistrin. TRAAW was calculated on histology as the ratio of whole arcuate artery section area divided by the area of the lumen. Differences between PTACE2KO and controls were assessed using two-sided t-test within each sex.

Results

35 mice underwent sham or CA/CPR. 49-day survival rate after CA/CPR overall was 67%, 71% in males and 62% in females (p=0.70 with Fisher’s exact test). Time between CA-induction and resuscitation, 49-day survival rate, and body, heart, and kidney weight on day 49 were similar between the strains in both sexes. In shams, GFR was not different by strain (882±100 in PTACE2KO and 872±61 in controls, p=0.91 in males, 993±3.2 and 1094±74, respectively, p=0.30, in females). 49 days after CA/CPR, GFR of male PTACE2KO was unexpectedly higher compared to male controls (953±94 and 743±142, p=0.03). However, GFR of female PTACE2KO was not different from controls, although trending lower (701±120 and 985±208, p=0.07). Interaction of the strain and sex for GFR was significant with two-way ANOVA (p=0.005). TRAAW was reduced in male PTACE2KO compared to controls, which demonstrated smooth muscle hyperplasia (1.52±0.15 and 2.37±0.35, p<0.001), while it was not different in females (2.82±0.91 in PTACE2KO and 2.47±0.47 in controls, p=0.27).

Conclusion

ACE2 deletion in PT attenuates CA/CPR-induced late GFR loss and arteriolar hyperplasia in males, but not in females.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025gvfykyv2