# Post‐ischemia and reperfusion kidney injury is mitigated in a novel complement 5 knockout rat

## TL;DR

A new rat model lacking complement 5 shows reduced kidney injury after ischemia-reperfusion, suggesting complement 5 plays a harmful role in this process.

## Contribution

A novel CRISPR/Cas9-generated C5−/− rat model is introduced to study complement 5's role in kidney injury.

## Key findings

- C5−/− rats showed improved kidney function and reduced apoptosis after IRI.
- C5−/− rats had increased NK cells, B cells, and CD8+ T-cells post-injury.
- Renal sections from C5−/− rats showed reduced immune cell infiltration.

## Abstract

Ischemia‐reperfusion injury (IRI) is the central contributing factor to acute kidney injury (AKI). Kidney tissue that becomes necrotic during this process releases a variety of pro‐inflammatory factors, driving activation of the complement cascade. Complement 5 (C5), in particular, has become an important therapeutic target, yet pharmacologic targeting does not achieve complete inhibition nor target all variants of this abundant protein. Here, we have generated and characterized a novel rat model of CRISPR/Cas9‐mediated global C5 deletion (C5−/−). C5−/− rats displayed no differences in growth, blood chemistry, or kidney morphology/function from wild‐type (C5+/+) counterparts at baseline. Subsequently, we compared C5−/− rats to C5+/+ littermates in a renal IRI model to assess differences in the post‐injury response. Compared to C5+/+, C5−/− rats displayed significantly improved kidney injury/function as well as the attenuation of the apoptotic pathway post‐IRI. The circulating immune cell composition was affected by C5−/− post‐injury, with significantly increased NK cells, B cells, and CD8+ T‐cells compared to C5+/+, indicating altered inflammatory signaling. Similarly, renal sections showed a reduced level of immune cell infiltration, including macrophages and neutrophils. Collectively, these results demonstrate the generation of an effective rodent model of global C5 deletion and the role of C5 as an injury‐promoting molecule during kidney IRI.