Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy

被引：388

作者：

Shahzad, Khurrum ^{[1
,2
]}

Bock, Fabian ^{[1
,3
]}

Dong, Wei ^{[1
]}

Wang, Hongjie ^{[1
,4
]}

Kopf, Stefan ^{[3
]}

Kohli, Shrey ^{[1
]}

Al-Dabet, Moh'd Mohanad ^{[1
]}

Ranjan, Satish ^{[1
]}

Wolter, Juliane ^{[1
]}

Wacker, Christian ^{[1
]}

Biemann, Ronald ^{[1
]}

Stoyanov, Stoyan ^{[5
]}

Reymann, Klaus ^{[5
]}

Soderkvist, Peter ^{[6
]}

Gross, Olaf ^{[7
]}

Schwenger, Vedat ^{[8
]}

Pahernik, Sascha ^{[9
,10
]}

Nawroth, Peter P. ^{[3
]}

Groene, Herman-Josef ^{[11
]}

Madhusudhan, Thati ^{[1
]}

Isermann, Berend ^{[1
]}

机构：

[1] Otto Von Guericke Univ, Dept Clin Chem & Pathobiochem, Inst Clin Pathol & Pathobiochem, D-39120 Magdeburg, Germany

[2] Univ Hlth Sci, Lahore, Pakistan

[3] Heidelberg Univ, Dept Internal Med & Clin Chem 1, Heidelberg, Germany

[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Cardiol, Wuhan 430074, Peoples R China

[5] German Ctr Neurodegenerat Dis DZNE, Magdeburg, Germany

[6] Linkoping Univ, Dept Clin & Expt Med, Div Cell Biol, Fac Hlth Sci, Linkoping, Sweden

[7] Tech Univ Munich, Klinikum Rechts Isar, Inst Klin Chem & Pathobiochem, D-80290 Munich, Germany

[8] Heidelberg Univ, Dept Nephrol, Heidelberg, Germany

[9] Heidelberg Univ, Dept Urol, Heidelberg, Germany

[10] Heidelberg Univ, Natl Ctr Tumor Dis, Tissue Bank, Heidelberg, Germany

[11] German Canc Res Ctr, Dept Cellular & Mol Pathol, Heidelberg, Germany

来源：

KIDNEY INTERNATIONAL | 2015年 / 87卷 / 01期

关键词：

diabetic nephropathy; endothelial cell; inflammasome; mitochondrial ROS; Nlrp3; podocyte; BONE-MARROW ORIGIN; NLRP3; INFLAMMASOME; OXIDATIVE STRESS; MITOCHONDRIAL SUPEROXIDE; PODOCYTE INJURY; DENDRITIC CELLS; KIDNEY-DISEASE; NADPH OXIDASE; MAJOR SOURCE; MOUSE;

D O I：

10.1038/ki.2014.271

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

引用

页码：74 / 84

页数：11

共 58 条

[31] Lymphocytes promote albuminuria, but not renal dysfunction or histological damage in a mouse model of diabetic renal injury [J].