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Generation of a novel decay accelerating factor (DAF) knock-out rat model using clustered regularly-interspaced short palindromic repeats, (CRISPR)/associated protein 9 (Cas9), genome editing

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Abstract

Decay accelerating factor (DAF), a key complement activation control protein, is a 70 kDa membrane bound glycoprotein which controls extent of formation of the C3 and C5 convertases by accelerating their decay. Using clustered regularly-interspaced short palindromic repeats, (CRISPR)/associated protein 9 (Cas9) genome editing we generated a novel DAF deficient (Daf−/−) rat model. The present study describes the renal and extrarenal phenotype of this model and assesses renal response to complement-dependent injury induced by administration of a complement-fixing antibody (anti-Fx1A) against the glomerular epithelial cell (podocyte). Rats generated were healthy, viable and able to reproduce normally. Complete absence of DAF was documented in renal as well as extra-renal tissues at both protein and mRNA level compared to Daf+/+ rats. Renal histology in Daf−/− rats showed no differences regarding glomerular or tubulointerstitial pathology compared to Daf+/+ rats. Moreover, there was no difference in urine protein excretion (ratio of urine albumin to creatinine) or in serum creatinine and urea levels. In Daf−/− rats, proteinuria was significantly increased following binding of anti-Fx1A antibody to podocytes while increased C3b deposition was observed. The DAF knock-out rat model developed validates the role of this complement cascade regulator in immune-mediated podocyte injury. Given the increasing role of dysregulated complement activation in various forms of kidney disease and the fact that the rat is the preferred animal for renal pathophysiology studies, the rat DAF deficient model may serve as a useful tool to study the role of this complement activation regulator in complement-dependent forms of kidney injury.

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Acknowledgements

This work is relevant to work proposed in a Veterans Affairs Merit Award to E. A. L, and was supported by funds from the Gene Editing Rat Resource Center of the Medical College of Wisconsin. We thank Z. Kollia for her assistance with animal work described in the study.

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Authors and Affiliations

  1. 1st Department of Critical Care Medicine and Pulmonary Services, School of Medicine, Evangelismos Hospital, G.P. Livanos and M. Simou Laboratories, National and Kapodistrian University of Athens, 3 Ploutarchou Street, 10675, Athens, Greece

    Maria G. Detsika & K. Goudevenou

  2. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA

    A. M. Geurts

  3. Department of Pathology, University of Athens School of Medicine, Athens, Greece

    H. Gakiopoulou

  4. Department of Nephrology, School of Medicine, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece

    E. Grapsa

  5. Veterans Affairs Medical Center and Virginia Tech. Carilion School of Medicine, 1970 Roanoke Blvd., Salem, VA, 24153, USA

    Elias A. Lianos

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  1. Maria G. Detsika
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  2. K. Goudevenou
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  3. A. M. Geurts
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  4. H. Gakiopoulou
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  5. E. Grapsa
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  6. Elias A. Lianos
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Correspondence to Maria G. Detsika.

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Detsika, M.G., Goudevenou, K., Geurts, A.M. et al. Generation of a novel decay accelerating factor (DAF) knock-out rat model using clustered regularly-interspaced short palindromic repeats, (CRISPR)/associated protein 9 (Cas9), genome editing. Transgenic Res 30, 11–21 (2021). https://doi.org/10.1007/s11248-020-00222-x

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