- Zhang, Shungang; Breidenbach, Joshua D; Khalaf, Fatimah K; Dube, P R; Mohammed, Chrysan J; Lad, Apurva; Stepkowski, Stanislaw; Hinds, Terry D; Kumarasamy, Sivarajan; Kleinhenz, Andrew; Tian, Jiang; Malhotra, Deepak; Kennedy, David J; Cooper, Christopher J; Haller, S T
- 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 CD40 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 CD40 function is abolished (). Methods and Results Four weeks following the 2-kidney 1-clip procedure, 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 rats versus S rat controls (46.2±1.9 versus 118.4±5.3 mg/24 h; <0.01), as well as protection from oxidative stress, as indicated by increased paraoxonase activity in rats versus S rat controls (<0.01). Ischemic kidneys from rats demonstrated a significant decrease in gene expression of the profibrotic mediator, plasminogen activator inhibitor-1 (<0.05), and the proinflammatory mediators, C-C motif chemokine ligand 19 (<0.01), C-X-C Motif Chemokine Ligand 9 (<0.01), and interleukin-6 receptor (<0.001), compared with S rat ischemic kidneys, as assessed by quantitative PCR assay. Reciprocal renal transplantation documented that CD40 exclusively expressed in the kidney contributes to ischemia-induced renal fibrosis. Furthermore, human CD40-knockout proximal tubule epithelial cells suggested that suppression of CD40 signaling significantly inhibited expression of proinflammatory and -fibrotic genes. Conclusions Taken together, our data suggest that activation of CD40 induces a significant proinflammatory and -fibrotic response and represents an attractive therapeutic target for treatment of ischemic renal disease.
Additional Document Info