Receptor activator of NF-kappaB and podocytes: towards a function of a novel receptor-ligand pair in the survival response of podocyte injury

• Published in: PloS one Vol. 7; no. 7; p. e41331
• Main Authors: Liu, Shuangxin, Shi, Wei, Xiao, Houqin, Liang, Xinling, Deng, Chunyu, Ye, Zhiming, Mei, Ping, Wang, Suxia, Liu, Xiaoying, Shan, Zhixin, Liang, Yongzheng, Zhang, Bin, Wang, Wenjian, Liu, Yanhui, Xu, Lixia, Xia, Yunfeng, Ma, Jianchao, Li, Zhilian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.07.2012; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Apoptosis - drug effects; Biology; Bone marrow; Cell Line, Transformed; Cell Survival - drug effects; Coordination compounds; Cytokines; Cytoplasm; Diabetes; Disease; Disease Models, Animal; Feet; Female; Gene expression; Gene Expression Regulation - drug effects; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulosclerosis, Focal Segmental - pathology; Glomerulus; Growth factors; Hospitals; Humans; Immunoelectron microscopy; Immunofluorescence; Injury prevention; Ischemia; Kidney Glomerulus - injuries; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidneys; Kinases; Ligands; Male; Medical research; Medicine; Metastasis; Mice; Mice, SCID; Microscopy; Nephrology; Nephrosis - chemically induced; Nephrosis - metabolism; Nephrosis - pathology; NF-κB protein; Osteoprotegerin; Pathogenesis; Pathology; Podocytes - metabolism; Podocytes - pathology; Prostate cancer; Proteins; Puromycin; Puromycin - adverse effects; Puromycin - pharmacology; RANK Ligand - metabolism; Rats; Receptor Activator of Nuclear Factor-kappa B - metabolism; Ribonucleic acid; RNA; RNA-mediated interference; Rodents; siRNA; Survival; TRANCE protein; Tumor necrosis factor; Tumor necrosis factor receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041331

Glomerulosclerosis correlates with reduction in podocyte number that occurs through mechanisms which include apoptosis. Podocyte injury or podocyte loss in the renal glomerulus has been proposed as the crucial mechanism in the development of glomerulosclerosis. However, the mechanism by which podocytes respond to injury is poorly understood. TNF and TNF receptor superfamilies are important in the pathogenesis of podocyte injury and apoptosis. The ligand of receptor activator of NF-kappaB (RANKL) and receptor activator of NF-kappaB (RANK) are members of the TNF and receptor superfamilies. We investigated whether RANK-RANKL is a receptor-ligand complex for podocytes responding to injury. In this study, RANKL and RANK were examined in human podocyte diseases and a rat model of puromycin aminonucleoside nephrosis (PAN). Compared with controls, RANK and RANKL were increased in both human podocyte diseases and the rat PAN model; double immunofluorescence staining revealed that RANK protein expression was mainly attributed to podocytes. Immunoelectron microscopy showed that RANK was localized predominantly at the top of the foot process membrane and the cytoplasm of rat podocyte. In addition, RANK was upregulated in mouse podocytes in vitro after injury induced by puromycin aminonucleoside (PA). Knockdown of RANK expression by small interference RNA (siRNA) exacerbated podocyte apoptosis induced by PA. However, RANKL inhibited significantly the apoptosis of podocytes induced by PA. These findings suggest the increase in RANK-RANKL expression is a response to podocyte injury, and RANK-RANKL may be a novel receptor-ligand complex for the survival response during podocyte injury.