Creation and characterization of a renin knockout rat.

Abstract

The renin-angiotensin system plays an important role in the control of blood pressure (BP) and renal function. To illuminate the importance of renin in the context of a disease background in vivo, we used zinc-finger nucleases (ZFNs) designed to target the renin gene and create a renin knockout in the SS/JrHsdMcwi (SS) rat. ZFN against renin caused a 10-bp deletion in exon 5, resulting in a frameshift mutation. Plasma renin activity was undetectable in the Ren-/- rat, and renin protein was absent from the juxtaglomerular cells in the kidney. Body weight was lower in the Ren-/- rats (than in the Ren+/- or wild-type littermates), and conscious BP on low-salt diet (0.4% NaCl) was 58 ± 2 mm Hg in the Ren-/- male rats versus 117 mm Hg in the Ren+/- littermates, a reduction of almost 50 mm Hg. Blood urea nitrogen (BUN) and plasma creatinine levels were elevated in the Ren-/- strain (BUN 112 ± 7 versus 23 ± 2 mg/dL and creatinine 0.53 ± 0.02 versus 0.26 ± 0.02 mg/dL), and kidney morphology was abnormal with a rudimentary inner renal medulla, cortical interstitial fibrosis, thickening of arterial walls, and abnormally shaped glomeruli. The development of the first rat knockout in the renin-angiotensin system demonstrates the efficacy of the ZFN technology for creating knockout rats for cardiovascular disease on any genetic background and emphasizes the role of renin in BP regulation and kidney function even in the low-renin SS rat.