Jang Hee-Seong, Kim Jee In, Noh Mira, Rhee Man Hee, Park Kwon Moo
Department of Anatomy, Cardiovascular Research Institute, BK21 Plus Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
Department of Molecular Medicine and Obesity-Mediated Disease Research Center, College of Medicine, Keimyung University, Daegu, 704-701, Republic of Korea.
Biochim Biophys Acta. 2014 Sep;1842(9):1733-41. doi: 10.1016/j.bbadis.2014.06.022. Epub 2014 Jun 26.
The regulator of G protein signaling 2 (RGS2) is a potent negative regulator of Gq protein signals including the angiotensin II (AngII)/AngII receptor signal, which plays a critical role in the progression of fibrosis. However, the role of RGS2 on the progression of kidney fibrosis has not been assessed. Here, we investigated the role of RGS2 in kidney fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO resulted in increased expression of RGS2 mRNA and protein in the kidney along with increases of AngII and its type 1 receptor (AT1R) signaling and fibrosis. Furthermore, UUO increased the levels of F4/80, Ly6G, myeloperoxidase, and CXCR4 in the kidneys. RGS2 deficiency significantly enhanced these changes in the kidney. RGS2 deletion in the bone marrow-derived cells by transplanting the bone marrow of RGS2 knock-out mice into wild type mice enhanced UUO-induced kidney fibrosis. Overexpression of RGS2 in HEK293 cells, a human embryonic kidney cell line, and RAW264.7 cells, a monocyte/macrophage line, inhibited the AngII-induced activation of ERK and increase of CXCR4 expression. These findings provide the first evidence that RGS2 negatively regulates the progression of kidney fibrosis following UUO, likely by suppressing fibrogenic and inflammatory responses through the inhibition of AngII/AT1R signaling.
G蛋白信号调节因子2（RGS2）是Gq蛋白信号的强效负调节因子，包括血管紧张素II（AngII）/AngII受体信号，其在纤维化进展中起关键作用。然而，RGS2在肾纤维化进展中的作用尚未得到评估。在此，我们研究了RGS2在小鼠单侧输尿管梗阻（UUO）诱导的肾纤维化中的作用。UUO导致肾脏中RGS2 mRNA和蛋白表达增加，同时AngII及其1型受体（AT1R）信号传导和纤维化增加。此外，UUO增加了肾脏中F4/80、Ly6G、髓过氧化物酶和CXCR4的水平。RGS2缺乏显著增强了肾脏中的这些变化。通过将RGS2基因敲除小鼠的骨髓移植到野生型小鼠中，使骨髓来源细胞中的RGS2缺失，增强了UUO诱导的肾纤维化。在人胚肾细胞系HEK293细胞和单核细胞/巨噬细胞系RAW264.7细胞中过表达RGS2，抑制了AngII诱导的ERK激活和CXCR4表达增加。这些发现提供了首个证据，即RGS2可能通过抑制AngII/AT1R信号传导来抑制致纤维化和炎症反应，从而对UUO后的肾纤维化进展起负调节作用。
