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Kidney Week

Abstract: FR-PO731

Angiotensin-Converting Enzyme 2 in Delayed Graft Function After Kidney Transplantation

Session Information

  • Transplantation: Basic
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 2101 Transplantation: Basic

Authors

  • Cianfarini, Cosimo L., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wysocki, Jan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Jiao-Jing, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Ye, Minghao, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhang, Zheng Jenny, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Batlle, Daniel, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Delayed graft function (DGF) is a severe form of acute kidney injury occurring post kidney transplantation. There is clinical evidence that the renin angiotensin system (RAS) is overactive in DGF. Angiotensin converting enzyme 2 (ACE2) is a RAS enzyme abundantly present in the kidney and localized in the apical brush border of the proximal tubule where it metabolizes Angiotensin II (Ang II) to form Angiotensin 1-7 thereby protecting from undesirable Ang II accumulation. Here we studied the expression and distribution of ACE2 in a mouse model of DGF.

Methods

Syngeneic kidney transplantation was performed between male C57BL/6 mice using donor kidneys exposed to 3hrs of cold ischemia. The transplanted kidneys (n=9) were harvested 48hrs after surgery and stained for ACE2 by immunohistochemistry (IHC). ACE2 protein was assessed by Western Blot and enzymatic activity using a fluorogenic substrate. Molecular markers for kidney damage and inflammation were assessed by Real-Time PCR. Kidney Angiotensin II levels were measured by ELISA.

Results

In mice with DGF, BUN was increased above 100mg/dl and NGAL and KIM-1 were increased in the kidney cortex. Markers of inflammation and immune cell invasion (IL-6, MCP-1, CD68, CD11b) were increased as well. Kidney Ang II levels were increased 2-fold (1.6±0.2 vs 0.7±0.06 pg/mg total protein, p=0.001) and ACE2 staining by IHC revealed profound alterations in the distribution of apical tubular ACE2 as compared to the healthy contralateral kidney. Tubules were widened and filled with ACE2 positive material, particularly in the corticomedullary region. The medulla showed luminal deposition of ACE2 positive material whereas staining was totally absent in the healthy contralateral kidney. These alterations were associated with decreased kidney ACE2 protein (57±13 vs 100±13 ACE2/GAPDH, p=0.03) and decreased ACE2 enzymatic activity (7.4±0.5 vs 9.3±0.6 RFU/µg total protein/h, p=0.03).

Conclusion

In mice with DGF post kidney transplantation there is a striking maldistribution of tubular ACE2 with loss of apical membrane bound full-length ACE2 into the tubular lumen. This loss results in decreased kidney ACE2 protein, enzymatic activity and increased kidney Ang II. The deficiency of this protective enzyme suggests that its replenishment could have an important therapeutic implication for DGF.

Funding

  • Other NIH Support