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Updated: Jan 12, 2026
Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
Post-ischemia and reperfusion kidney injury is mitigated in a novel complement 5 knockout rat
Madison McGraw1, Amod Sharma1, Dinesh Bhattarai1
1Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
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.
Insights
Researchers developed a novel rat model lacking Complement 5 (C5). These rats showed significantly reduced kidney injury and inflammation after ischemia-reperfusion injury, highlighting C5
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI).
- The complement cascade, particularly Complement 5 (C5), is implicated in IRI pathogenesis.
- Current pharmacologic inhibition of C5 is incomplete and may not address protein variants.
Purpose of the Study:
- To generate and characterize a CRISPR/Cas9-mediated global C5 deletion rat model (C5-/-).
- To evaluate the role of C5 in renal IRI using this novel model.
- To assess the impact of C5 deficiency on kidney injury, apoptosis, and immune cell response post-IRI.
Main Methods:
- CRISPR/Cas9 gene editing was used to create C5-/- rats.
- Baseline characterization of C5-/- rats compared to wild-type (C5+/+) littermates.
- Renal IRI was induced, and outcomes including kidney function, apoptosis markers, and immune cell infiltration were assessed.
Main Results:
- C5-/- rats exhibited no baseline differences in growth, blood chemistry, or kidney function.
- Post-IRI, C5-/- rats showed significantly improved kidney injury and function compared to C5+/+ rats.
- C5 deficiency led to attenuated apoptosis, altered circulating immune cell composition (increased NK, B, CD8+ T cells), and reduced renal immune cell infiltration.
Conclusions:
- A functional rodent model for global C5 deletion was successfully generated.
- C5 plays a significant injury-promoting role in kidney IRI.
- Targeting C5 represents a promising therapeutic strategy for mitigating kidney IRI.
