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Kidney Week

Abstract: SA-PO191

ACE2 Overexpression Mediates Spatial Distribution of Pathologic Features in AKI

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Emathinger, Jacqueline M., Oregon Health & Science University School of Medicine, Portland, Oregon, United States
  • Robertson, Joshua A., Oregon Health & Science University School of Medicine, Portland, Oregon, United States
  • Nelson, Jonathan W., Oregon Health & Science University School of Medicine, Portland, Oregon, United States
  • Kung, Vanderlene Liu, Oregon Health & Science University School of Medicine, Portland, Oregon, United States
  • Hutchens, Michael, Portland VA Medical Center, Portland, Oregon, United States
  • Gurley, Susan B., Oregon Health & Science University School of Medicine, Portland, Oregon, United States
Background

Acute kidney injury (AKI) is a widespread health problem often caused by ischemia. Angiotensin II (AngII) drives pathologic changes in AKI. Angiotensin converting enzyme 2 (ACE2) metabolizes AngII and extinguishes its effects. While several studies have examined the role ACE2 plays in chronic kidney disease and hypertension, less is known about ACE2 in AKI. We hypothesize that ACE2 overexpression promotes recovery after AKI via AngII metabolism.

Methods

We use K18-hACE2 mice which overexpress human ACE2 in epithelial cells. Unilateral renal ischemia reperfusion (IRI, 25-min ischemia) with contralateral nephrectomy was performed on age-matched K18-hACE2 and wildtype (WT) littermates. Blood urea nitrogen (BUN), plasma creatinine (Cr), and histology was performed.

Results

Human hACE2 mRNA expression is increased in K18-hACE2 kidneys (53.5 ± 1.3-fold over WT mice; p<0.05, 1A). At baseline, there was no significant difference in kidney AngII content in K18-hACE2 mice (428.4 ± 307.0 fmol/g vs 246.6 ± 122.8 fmol/g; 1B).
24 hours after IRI, renal function (BUN and plasma Cr) was similarly decreased in WT and K18-hACE2 mice. Quantification of tubular injury revealed less brush border loss in the corticomedullary junction (CMJ) of K18-hACE2 kidneys (13.4 ± 11.6 in WT vs 4.3 ± 4.7, p<0.01, 2A, B). In the cortex, overexpression of hACE2 caused lower levels of necrosis (23.2 ± 14.0 vs 10.9 ± 11.1 in WT, p<0.01, 2C).

Conclusion

We show that K18-hACE2 mice are a valuable tool for understanding ACE2 in the context of kidney injury. Reduced brush border injury scores in CMJ, and lower cortical necrosis in K18-hACE2 mice following IRI suggests that ACE2 mediates regional differences in pathologic injury. Unchanged AngII at baseline may suggest that renal ACE2 mediates acute changes in AngII in association with control of spatial injury pattern. Examination of the injury and repair processes will elucidate the impact of ACE2 overexpression on injury mechanisms.

Funding

  • NIDDK Support