Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy

PLoS One. 2016 Oct 5;11(10):e0164135. doi: 10.1371/journal.pone.0164135. eCollection 2016.


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.

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism*
  • Kidney / metabolism
  • Macrophages / metabolism
  • Mice
  • Signal Transduction
  • Up-Regulation


  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-1beta
  • NLRC4 protein, human