Genetic Modifiers of Mortality and Kidney Structure in Type 1a (AT1A) Angiotensin II Receptor Deficiency

Abstract

50 We have previously reported significant background gene effects on the phenotype of mice with targeted deletion of the AT 1A receptor gene ( Agtr1a ). On 129 or C57BL/6 backgrounds, most Agtr1a-/- mice die before weaning and those that survive develop marked abnormalities of kidney structure, including atrophy of the renal papilla and medial thickening of small renal arteries. In contrast, peri-natal survival and kidney structure are normal in F 1 (C57BL/6 x 129) Agtr1a-/- animals, suggesting that there are distinct recessive genetic modifiers on both the C57BL/6 and 129 backgrounds that modulate the phenotype of AT 1A receptor-deficiency. To further explore the characteristics of these modifying loci, we performed inter-crosses between F 1 (C57BL/6 x 129) Agtr1a- /- mice and evaluated the phenotypes of the resulting F2 Agtr1a-/- progeny. A simple model of two recessive modifier loci, one from each strain with complete penetrance, predicts that 44% of these F2 animals should manifest the trait of interest (either mortality or vascular pathology). Among 70 consecutive F2 progeny, only 4 pups were lost between birth and 21 days of age (94% survival). On pathological examination of the surviving mice, 33 or 50% had typical renal vascular pathology, while the remaining 33 had normal renal vessels. The frequency of post-natal mortality was significantly less than that predicted by this 2 locus model (p<0.0003 by chi-square), suggesting that there are multiple modifying loci for this trait. On the other hand, for renal vascular pathology, the observed number of affected F2 animals (50%) was not significantly different from the number predicted by our hypothetical model (p=0.31 by chi-square). These findings support a model of two distinct recessive modifier loci, one from each strain, that confer susceptibility to vascular pathology. Efforts are underway to indentify these genetic modifiers by genomic micro-satellite analysis.