ASK1/p38‑mediated NLRP3 inflammasome signaling pathway contributes to aberrant retinal angiogenesis in diabetic retinopathy

Int J Mol Med. 2021 Feb;47(2):732-740. doi: 10.3892/ijmm.2020.4833. Epub 2020 Dec 24.

Abstract

Diabetic retinopathy (DR) is the leading cause of blindness among the working‑age population in several countries. Despite the available treatments, some patients are diagnosed at the late stages of the disease when treatment is more difficult. Hence, it is crucial that novel targets are identified in order to improve the clinical therapy of DR. In the present study, an animal model of DR and a cell model using primary human retinal microvascular endothelial cells exposed to high glucose were constructed to examine the association between apoptosis signal‑regulating kinase 1 (ASK1)/p38 and NLR family pyrin domain containing 3 (NLRP3) in DR. The results revealed that DR induced inflammatory response and microvascular cell proliferation. NLRP3 contributed to DR‑mediated inflammatory development and progression, which promoted the expression of inflammatory‑related cytokines. In addition, NLRP3 promoted the tube formation of retinal microvascular endothelial cells and angiogenesis. Moreover, further research indicated that the NLRP3‑mediated aberrant retinal angiogenesis in DR was regulated by ASK1 and p38. It was thus suggested that ASK1/p38 may be novel target for the treatment of DR.

Keywords: diabetic retinopathy; inflammatory; ASK1/p38; NLRP3; angiogenesis.

MeSH terms

  • Animals
  • Diabetic Retinopathy / genetics
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Humans
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Male
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / metabolism*
  • Retinal Neovascularization / pathology
  • Signal Transduction*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse