Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy

Fang Yuan; Ryan Kolb; Gaurav Pandey; Wei Li; Lin Sun; Fuyou Liu; Fayyaz S Sutterwala; Yinghong Liu; Weizhou Zhang

doi:10.1371/journal.pone.0164135

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Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy

Journal article

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Peer reviewed

Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy

Fang Yuan, Ryan Kolb, Gaurav Pandey, Wei Li, Lin Sun, Fuyou Liu, Fayyaz S Sutterwala, Yinghong Liu and Weizhou Zhang

PloS one, Vol.11(10), pp.e0164135-e0164135

2016

DOI: 10.1371/journal.pone.0164135

PMCID: PMC5051905

PMID: 27706238

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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.

Signal Transduction

Calcium-Binding Proteins - metabolism

Up-Regulation

Inflammasomes - metabolism

Diabetic Nephropathies - metabolism

Humans

Diabetic Nephropathies - genetics

Disease Progression

Inflammasomes - genetics

CARD Signaling Adaptor Proteins - genetics

CARD Signaling Adaptor Proteins - metabolism

Kidney - metabolism

Macrophages - metabolism

Animals

Interleukin-1beta - metabolism

Mice

Calcium-Binding Proteins - genetics

Disease Models, Animal

Details

Title: Subtitle: Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy
Creators: Fang Yuan - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
Ryan Kolb - Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
Gaurav Pandey - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
Wei Li - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
Lin Sun - Department of Nephrology, the Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan China
Fuyou Liu - Department of Nephrology, the Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan China
Fayyaz S Sutterwala - Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
Yinghong Liu - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
Weizhou Zhang - Cancer Genes and Pathway Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.11(10), pp.e0164135-e0164135
DOI: 10.1371/journal.pone.0164135
PMID: 27706238
PMCID: PMC5051905
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: R00 CA158055 / NCI NIH HHS R01 CA203834 / NCI NIH HHS K99 CA158055 / NCI NIH HHS R01 CA200673 / NCI NIH HHS T32 AI007260 / NIAID NIH HHS
Language: English
Date published: 2016
Academic Unit: Radiation Oncology
Record Identifier: 9984083877602771

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