Renal Fibrosis Is Significantly Attenuated Following Targeted Disruption of Cd40 in Experimental Renal Ischemia Article (Web of Science)


  • Background Renal artery stenosis is a common cause of renal ischemia, contributing to the development of chronic kidney disease. To investigate the role of local CD 40 expression in renal artery stenosis, Goldblatt 2‐kidney 1‐clip surgery was performed on hypertensive Dahl salt‐sensitive rats (S rats) and genetically modified S rats in which CD 40 function is abolished ( Cd40 mutant ). Methods and Results Four weeks following the 2‐kidney 1‐clip procedure, Cd40 mutant rats demonstrated significantly reduced blood pressure and renal fibrosis in the ischemic kidneys compared with S rat controls. Similarly, disruption of Cd40 resulted in reduced 24‐hour urinary protein excretion in Cd40 mutant rats versus S rat controls (46.2±1.9 versus 118.4±5.3 mg/24 h; P <0.01), as well as protection from oxidative stress, as indicated by increased paraoxonase activity in Cd40 mutant rats versus S rat controls ( P <0.01). Ischemic kidneys from Cd40 mutant rats demonstrated a significant decrease in gene expression of the profibrotic mediator, plasminogen activator inhibitor‐1 ( P <0.05), and the proinflammatory mediators, C‐C motif chemokine ligand 19 ( P <0.01), C‐X‐C Motif Chemokine Ligand 9 ( P <0.01), and interleukin‐6 receptor ( P <0.001), compared with S rat ischemic kidneys, as assessed by quantitative PCR assay. Reciprocal renal transplantation documented that CD 40 exclusively expressed in the kidney contributes to ischemia‐induced renal fibrosis. Furthermore, human CD 40‐knockout proximal tubule epithelial cells suggested that suppression of CD 40 signaling significantly inhibited expression of proinflammatory and ‐fibrotic genes. Conclusions Taken together, our data suggest that activation of CD 40 induces a significant proinflammatory and ‐fibrotic response and represents an attractive therapeutic target for treatment of ischemic renal disease.


publication date

  • 2020


  • 9


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