Department of Physiology (M.L.R., J.J.R., M.A.O., K.B., K.K.W., D.T.B., K.-T.L., P.N., C.D.S., J.L.G.), Neuroscience Research Center, Medical College of Wisconsin, Milwaukee.
Medical College of Wisconsin, Milwaukee. Department of Pharmacology and Neuroscience (G.D., Y.D., S.A.S., H.C.), University of Iowa, Iowa City.
Hypertension. 2022 Dec;79(12):2843-2853. doi: 10.1161/HYPERTENSIONAHA.122.20169. Epub 2022 Oct 19.
RGS (regulator of G protein signaling) family members catalyze the termination of G protein signaling cascades. Single nucleotide polymorphisms in the gene in humans have been linked to hypertension, preeclampsia, and anxiety disorders. Mice deficient for ) exhibit hypertension, anxiety, and altered adipose development and function.
To study cell-specific functions of RGS2, a novel gene-targeted mouse harboring a conditional allele for the gene () was developed. These mice were bred with mice expressing Cre-recombinase via the Agouti-related peptide locus (-Cre) to cause deletion of from all cells expressing ), or a novel transgenic mouse expressing Cre-recombinase via the ANG (angiotensin) type 1A receptor (/ AT) promoter encoded in a bacterial artificial chromosome (BAC-AT-Cre) to delete in all -expressing cells ().
Whereas , , and BAC-AT-Cre mice exhibited normal growth and survival, exhibited pre-weaning lethality. Relative to littermates, exhibited reduced fat gains when maintained on a high fat diet, associated with increased energy expenditure. Similarly, surviving adult mice also exhibited increased energy expenditure. Surprisingly, given the hypertensive phenotype previously reported for mice and evidence supporting a role for RGS2 in terminating AT signaling in various cell types, mice exhibited normal blood pressure, ingestive behaviors, and renal functions, both before and after chronic infusion of ANG (490 ng/kg/min, sc).
These results demonstrate the development of a novel mouse with conditional expression of and illustrate the role of within selected cell types for cardiometabolic control.
RGS（G 蛋白信号转导调节因子）家族成员催化 G 蛋白信号级联反应的终止。人类中基因的单核苷酸多态性与高血压、先兆子痫和焦虑障碍有关。缺乏基因的小鼠表现出高血压、焦虑以及脂肪组织发育和功能改变。
为了研究 RGS2 的细胞特异性功能，开发了一种新型基因靶向小鼠，该小鼠携带用于基因的条件性等位基因（）。这些小鼠与通过 Agouti 相关肽基因座（）表达 Cre 重组酶的小鼠杂交，以导致所有表达的细胞中缺失基因（），或与通过细菌人工染色体（BAC-AT-Cre）表达 Cre 重组酶的新型转基因小鼠杂交，该小鼠在所有表达的细胞中缺失基因（）。
尽管、和 BAC-AT-Cre 小鼠表现出正常的生长和存活，但小鼠表现出新生期致死性。与同窝仔相比，当维持高脂肪饮食时，表现出脂肪积累减少，伴随着能量消耗增加。同样，幸存的成年小鼠也表现出能量消耗增加。令人惊讶的是，鉴于先前报道的小鼠高血压表型以及支持 RGS2 在各种细胞类型中终止 AT 信号的证据，表现出正常的血压、摄食行为和肾功能，无论是在慢性 ANG（490 ng/kg/min，sc）输注之前还是之后。
这些结果证明了一种新型具有条件性表达的小鼠的开发，并说明了在选定细胞类型中对心脏代谢控制的作用。
