Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy

• Published in: PloS one 2016-10, Vol.11 (10), p.e0164135-e0164135
• Main Authors: Yuan, Fang, Kolb, Ryan, Pandey, Gaurav, Li, Wei, Sun, Lin, Liu, Fuyou, Sutterwala, Fayyaz S, Liu, Yinghong, Zhang, Weizhou
• Format: Article
• Language: English
• Subjects: Activation; Adapter proteins; Albumin; Animals; Biology and Life Sciences; Blood glucose; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cancer; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Chronic kidney failure; Cytokines; Diabetes; Diabetes mellitus; Diabetic nephropathies; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Disease; Disease Models, Animal; Disease Progression; End-stage renal disease; Excretion; Histology; Hospitals; Humans; IL-1β; Immunology; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Interdisciplinary aspects; Interleukin; Interleukin-1beta - metabolism; Interleukins; Kidney - metabolism; Kidney diseases; Kidneys; Kinases; Macrophages; Macrophages - metabolism; MAP kinase; Medical treatment; Medicine; Medicine and Health Sciences; Metabolism; Mice; Nephrology; Nephropathy; NF-κB protein; Obesity; Pathogens; Pathology; Pathways; Research and Analysis Methods; Rodents; Signal Transduction; Signaling; Transplants & implants; Type 2 diabetes; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0164135

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. The role of inflammation in DN has only recently been recognized. It has been shown that the NLRP3-inflammasome contributes to DN development by inducing interleukin (IL)-1β processing and secretion. In an effort to understand other IL-1β activating mechanism during DN development, we examined the role of the NLRC4-inflammasome in DN and found that NLRC4 is a parallel mechanism, in addition to the NLRP3-inflammasome, to induce pro-IL-1β processing and activation. We found that the expression of NLRC4 is elevated in DN kidneys. NLRC4-deficiency results in diminished DN disease progression, as manifested by a decrease in blood glucose and albumin excretion, as well as preserved renal histology. We further found that DN kidneys have increased F4/80+ macrophages, increased IL-1β production, and other signaling pathways related to kidney pathology such as activation of NF-κB and MAP kinase pathways, all of which were rescued by NLRC4-deficiency. This study demonstrates NLRC4-driven IL-1β production as critical for the progression of DN, which underscores the importance to target this pathway to alleviate this devastating disease.