Affiliation:
1. Department of Medicine University of Toledo College of Medicine and Life Sciences Toledo OH
2. Department of Medical Microbiology and Immunology University of Toledo College of Medicine and Life Sciences Toledo OH
3. Department of Physiology and Pharmacology University of Toledo College of Medicine and Life Sciences Toledo OH
Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
9 articles.
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