Kidney Week

Abstract: FR-PO195

Expression and Functional Effect of ACE2 in Heme Protein-Mediated AKI (HP-AKI) in Rodents

Session Information

• AKI: Mechanisms
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Croatt, Anthony J., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States

Anthony J. Croatt

• Singh, Raman Deep, Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States

Raman Deep Singh, MS, PhD

• Ackerman, Allan W., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States

Allan W. Ackerman

• Nath, Karl A., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States

Karl A. Nath, MBChB

Background

Our prior study demonstrated that ACE2 expression is markedly reduced following acute renal ischemia (IRI-AKI) [Kidney360 2(7):p 1095-1106, 2021]. As ACE2 has previously been shown to be protective in IRI, we now investigate whether a similar expression profile exists in HP-AKI, and the functional significance of ACE2 in this model.

Methods

The glycerol model of HP-AKI was induced in Sprague Dawley rats and C57BL/6J mice by intramuscular injection (6 and 5 mL/kg, respectively). ACE2^+/+ and ACE2^-/- mice were also subjected to HP-AKI (6 mL/kg). Assessments of ACE2 mRNA and protein expression were performed, as well as measurements of renal ACE2 activity. Assessments of renal functional markers (serum creatinine and BUN) were also undertaken.

Results

In the rat, ACE2 mRNA and protein were both reduced significantly at 1 day after induction of HP-AKI. At 2 days after HP-AKI, ACE2 protein expression and activity were both markedly reduced (by approximately 50% and 36%, respectively). In the mouse, ACE2 mRNA expression was reduced at 1 day post HP-AKI induction (8.4±1.0 vs 4.2±0.4, P=0.0013), but was not significantly altered at 8 hours after HP-AKI induction. Serum creatinine following HP-AKI was significantly lower in ACE2^-/- mice, compared with ACE2^+/+ mice (2.2±0.1 vs 2.7±0.1 mg/dL, P=0.0096). BUN levels, however, were not significantly different between ACE2^+/+ and ACE2^-/- mice subjected to HP-AKI at this time point.

Conclusion

As in our previous IRI-AKI studies, the present rat and mouse studies show that ACE2 mRNA, protein, and activity levels are all significantly reduced after HP-AKI induction (as early as 1 day and through at least 2 days). In contrast to prior studies showing that ACE2 deficiency exacerbates the IRI-AKI model, our studies failed to show a similar exacerbation in ACE2^-/- mice subjected to HP-AKI. Indeed, as assessed by 1 of 2 functional markers (serum creatinine), we observe a mild protective effect of ACE2 deficiency. These findings point to significant differences between IRI-AKI and HP-AKI as regards the functional roles of ACE2. Further study is required to delineate the basis for the reduced expression of ACE2 in HP-AKI and the functional significance of ACE2 in this model.

Funding

• NIDDK Support