Abstract 13449: Cd40 Contributes to Renal Fibrosis in Experimental Renal Ischemia
Introduction: Cd40 has been implicated in renal injury following activation by its ligand (sCD40L), which is released from activated platelets. Previously we have shown that patients with renal ischemia have elevated levels of sCD40L and circulating levels of CD40 predict changes in renal function. We created a novel Cd40 mutant on the background of the genetically hypertensive Dahl S rat (S rat), which is prone to the development of renal disease, in order to determine the role of Cd40 in ischemic renal disease.
Hypothesis: Cd40 induces renal fibrosis in renal ischemia.
Methods: A novel Cd40 mutant, with targeted disruption of Cd40, was created in the S rat using the zinc-finger nuclease method. Male Cd40 mutant rats weighing between 250-300 g were used (n=8). Eight S rats were used as age-matched controls. Western blot analysis, trichrome staining, and immunohistochemistry were performed on kidney tissue derived from Cd40 mutants and S rats four weeks following two-kidney one clip (2K1C) surgery. Renal function was determined by urinary protein excretion (UPE), and creatinine measurements.
Results: The Cd40 mutants when compared to S rats exhibited significantly lower systolic blood pressure four weeks following 2K1C surgery (130 ± 6 vs. 155 ± 4 mmHg, p<0.01). Kidney tissue derived from the clipped ischemic kidneys showed a substantial decrease in fibrosis in the Cd40 mutants compared to S rat controls as assessed by trichrome staining (p<0.01), which was confirmed by collagen-1 expression. The Cd40 mutants also exhibited a significant decrease in UPE (173.2 ± 18.8 vs. 230.6 ± 17.4 mg/24hrs, p<0.05) and creatinine (0.85 ± 0.03 vs. 1.00 ± 0.06 mg/dL, p<0.05) compared to S rat controls.
Conclusions: Mutation of the Cd40 gene decreases renal fibrosis and improves renal function following renal ischemia. Our results indicate that Cd40 contributes to ischemic renal fibrosis and provides a mechanistic rationale for the development of renal dysfunction in ischemic renal disease.
Author Disclosures: S.T. Haller: None. D.A. Folt: None. S. Kumarasamy: None. S. Upadhyaya: None. J.I. Shapiro: None. B. Joe: None. C.J. Cooper: None.
- © 2015 by American Heart Association, Inc.