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Kidney Week

Abstract: TH-PO092

Ischemia-Reperfusion-Mediated Kidney Injury Is Attenuated in a New Complement 5 Knockout Model

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mcgraw, Madison K., University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, United States
  • Bhattarai, Dinesh, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, United States
  • Lee, Seongok, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, United States
  • Parajuli, Nirmala, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, United States
Background

Acute kidney injury (AKI) affects over 13 million people each year around the world due to renal injury caused by ischemia. Additionally, 70% of transplanted kidneys are sourced from deceased donors, and organs are transported in static cold storage (CS) to maintain tissue viability, with the consequence of subjecting the kidney to ischemic conditions. Renal ischemia has been previously attributed to the aberrant activation of the complement system during AKI and transplant. The terminal cascade begins with the cleavage of complement 5 (C5) and drives downstream membrane attack complex (C5b-9) formation, but the role of this terminal pathway during renal ischemia is not fully understood.

Methods

In this preliminary study, we developed a novel C5 knockout (C5KO) rat model via CRISPR/Cas9 deletion of C5 exon 3. Furthermore, C5KO Lewis rats were introduced in a model of renal ischemia-reperfusion (I/R) via 40-minute bilateral clamping of the renal vessels and right nephrectomy. Animals were sacrificed day 1 post-procedure and characterized in terms of arterial blood gases/chemistry, mitochondrial respiration, and fluorescence activated cell sorting (FACS).

Results

We have observed a fertile animal with normal mitochondrial function and no health concerns. I/R resulted in significant elevation of serum creatinine (SCr) and blood urea nitrogen (BUN) in C5+/+ rats compared to sham (n=4 per group; p=0.0004 and 0.0019, respectively). This effect was attenuated by C5-/- for SCr (n=4; p=0.005) and BUN (n=4; p=0.0223). C5+/- also significantly decreased SCr (n=4; p=0.0165) after I/R when compared to C5+/+, but not BUN.

Conclusion

Knockout (or partial knockout) of complement component C5 results in a reduction in SCr and BUN during I/R compared to wild-type, suggesting that targeting C5 during kidney injury may confer a protective effect. This model may be useful in future studies focused on the role of C5 during AKI or CS+Tx.

Funding

  • NIDDK Support