Kadoya Hiroyuki, Satoh Minoru, Sasaki Tamaki, Taniguchi Shun'ichiro, Takahashi Masafumi, Kashihara Naoki
*Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
*Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; and Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
FASEB J. 2015 Sep;29(9):3899-910. doi: 10.1096/fj.15-271734. Epub 2015 Jun 8.
High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone-induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome. Infusing wild-type mice with aldosterone (0.25 mg/kg/d) caused tubulointerstitial damage, increased expression of inflammasome components, caspase 1 activation, and overproduction of IL-1β and IL-18. These changes were suppressed by eplerenone treatment (100 mg/kg/d) in wild-type mice or in mice deficient in apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC). Caspase 1-positive and F4/80-positive cells colocalized in the interstitium. Bone marrow transplantation using ASC-deficient mice indicated that inflammasome activation in macrophages mediated aldosterone-induced renal fibrosis. IL-18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria-derived reactive oxygen species activated the inflammasome in these macrophages. Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria-derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease.
高水平的醛固酮通过激活促炎和促纤维化途径损害肾功能。然而，醛固酮诱导炎症和纤维化的分子机制尚不清楚。炎性小体激活与慢性肾脏病有关。我们推测醛固酮通过激活炎性小体诱导肾小管间质炎症和纤维化。给野生型小鼠输注醛固酮（0.25毫克/千克/天）会导致肾小管间质损伤、炎性小体成分表达增加、半胱天冬酶-1激活以及白细胞介素-1β和白细胞介素-18过量产生。依普利酮治疗（100毫克/千克/天）可抑制野生型小鼠或缺乏含半胱天冬酶招募结构域的凋亡相关斑点样蛋白（ASC）的小鼠的这些变化。半胱天冬酶-1阳性细胞和F4/80阳性细胞在间质中共定位。使用ASC缺陷小鼠进行的骨髓移植表明，巨噬细胞中的炎性小体激活介导了醛固酮诱导的肾纤维化。在用醛固酮处理的巨噬细胞培养上清液中检测到白细胞介素-18，并且线粒体衍生的活性氧激活了这些巨噬细胞中的炎性小体。我们的结果表明，巨噬细胞暴露于高水平醛固酮会导致炎性小体通过线粒体衍生的活性氧被激活。因此，巨噬细胞中的炎性小体激活可能成为慢性肾脏病的一个新的治疗靶点。
