C3aR contributes to unilateral ureteral obstruction-induced renal interstitial fibrosis via the activation of the NLRP3 inflammasome.

Abstract

AIMS:

Complement component 3a and its receptor (C3a/C3aR) and nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome are involved in the pathogenesis of renal interstitial fibrosis (RIF). However, the mechanisms have not been clearly illuminated. This study aimed to elucidate the roles of C3aR and the NLRP3 inflammasome involved in unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis.

MAIN METHODS:

UUO models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950, an inhibitor of the NLRP3 inflammasome, was intraperitoneally injected in UUO mice. Blood samples were collected to quantify serum creatinine and urea. Kidney samples were collected for hematoxylin-eosin (HE), Masson, and immunohistochemistry staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and Western blotting.

KEY FINDINGS:

Renal function, renal fibrosis, and renal inflammation in WT mice were aggravated with longer periods of UUO. C3aR deficiency improved renal function and attenuated renal fibrosis and the activation of the NLRP3 inflammasome in UUO mice. Renal function and renal fibrosis in UUO mice were attenuated after NLRP3 inflammasome inhibition; however, the expression of C3aR did not change.

SIGNIFICANCE:

Our data revealed that C3aR may aggravate RIF by regulating the activation of the NLRP3 inflammasome (particularly regulating inflammasome assembly) in renal tubular epithelial cells in the UUO model.

• Authors: Danyu You, Mengjie Weng, Xiaoting Wu, Kun Nie, Jiong Cui, Yi Chen, Liyan Yang, Jianxin Wan
• Journal: Life sciences (Life Sci) Vol. 308 Pg. 120905 (Nov 01 2022) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 36041502 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Nucleotides
• Receptors, G-Protein-Coupled
• Complement C3a
• Urea
• Creatinine
• DNA Nucleotidylexotransferase
• Eosine Yellowish-(YS)
• Hematoxylin

Topics

• Animals
• Complement C3a (metabolism)
• Creatinine (metabolism)
• DNA Nucleotidylexotransferase (metabolism)
• Eosine Yellowish-(YS)
• Fibrosis
• Hematoxylin
• Inflammasomes (metabolism)
• Kidney (metabolism)
• Kidney Diseases (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Nucleotides (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Urea (metabolism)
• Ureteral Obstruction (pathology)