Gain-of-function variants in NLRP1 protect against the development of diabetic kidney disease: NLRP1 inflammasome role in metabolic stress sensing?

Jaine L S Soares; Fernanda Pereira Fernandes; Thiago Andrade Patente; Maria B Monteiro; Maria C Parisi; Daniel Giannella-Neto; Maria L Corrêa-Giannella; Alessandra Pontillo

doi:10.1016/j.clim.2017.10.003

Gain-of-function variants in NLRP1 protect against the development of diabetic kidney disease: NLRP1 inflammasome role in metabolic stress sensing?

Clin Immunol. 2018 Feb:187:46-49. doi: 10.1016/j.clim.2017.10.003. Epub 2017 Oct 12.

Authors

Jaine L S Soares¹, Fernanda Pereira Fernandes¹, Thiago Andrade Patente², Maria B Monteiro³, Maria C Parisi⁴, Daniel Giannella-Neto⁵, Maria L Corrêa-Giannella⁶, Alessandra Pontillo⁷

Affiliations

¹ Laboratório de Imunogenética, Departamento of Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo (USP), São Paulo, SP, Brazil.
² Laboratório de Imunologia dos Tumores, Departamento of Imunologia, Instituto de Ciências Biomédicas, USP, São Paulo, SP, Brazil.
³ Laboratório de Carboidratos e Radioimunoensaios (LIM-18), Faculdade de Medicina da USP, São Paulo, (SP, Brazil).
⁴ Divisão de Endocrinologia, Departamento de Clínica Médica, Faculdade de Medicina da Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
⁵ Programa de Pós-Graduação em Medicina, Universidade Nove de Julho - UNINOVE, São Paulo, SP, Brazil.
⁶ Laboratório de Carboidratos e Radioimunoensaios (LIM-18), Faculdade de Medicina da USP, São Paulo, (SP, Brazil); Programa de Pós-Graduação em Medicina, Universidade Nove de Julho - UNINOVE, São Paulo, SP, Brazil.
⁷ Laboratório de Imunogenética, Departamento of Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo (USP), São Paulo, SP, Brazil. Electronic address: alepontillo@usp.br.

PMID: 29031829
DOI: 10.1016/j.clim.2017.10.003

Abstract

Although inflammasome plays a well-known role in animal models of renal injury, limited studies in humans are available, and its participation in diabetic kidney disease (DKD) remains unknown. Aim of this study was to elucidate the contribution of inflammasome genetics in the development of DKD in type-1 diabetes (T1D). The association of functional variants in inflammasome genes with DKD was assessed by multivariate analysis in a retrospective and in a prospective cohort. NLRP1 rs2670660 and rs11651270 polymorphisms were significantly associated with a decrease risk to develop DKD (p_adj<0.01), and rs11651270 also with a lower risk of new renal events during follow-up (p_adj=0.01). Supporting these findings, diabetes metabolites (glycated albumin and high glucose) were able to modulate NLRP1 expression. This study is the first to suggest a protective role of NLRP1 in DKD, highlighting an emerging role of NLRP1 as a homeostatic factor against metabolic stress.

Keywords: Diabetic kidney disease; Inflammasome; NLRP1; SNPs; Type 1 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adult
Apoptosis Regulatory Proteins / genetics*
Blood Glucose / metabolism
Diabetes Mellitus, Type 1 / complications
Diabetes Mellitus, Type 1 / metabolism*
Diabetic Nephropathies / etiology
Diabetic Nephropathies / genetics*
Female
Gain of Function Mutation
Genetic Predisposition to Disease
Glycated Serum Albumin
Glycation End Products, Advanced
Humans
Inflammasomes / genetics
Male
Middle Aged
Multivariate Analysis
NLR Proteins
Polymorphism, Single Nucleotide
Prospective Studies
Retrospective Studies
Serum Albumin / metabolism
Stress, Physiological
Young Adult

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
Blood Glucose
Glycation End Products, Advanced
Inflammasomes
NLR Proteins
NLRP1 protein, human
Serum Albumin
Glycated Serum Albumin