title: Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy.
abstract: 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.
authors.affiliation: Department of Nephrology, the Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan China.|Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.|Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kolb
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pandey
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Nephrology, the Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan China.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Nephrology, the Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan China.
authors.forename: Fuyou
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Nephrology, the Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan China.|Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.|Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.|Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.|Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.|Cancer Genes and Pathway Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; C435692:NLRC4 protein, human