Background: We explored the role of CD40 signaling in kidney proximal tubule epithelial cells on renal interstitial fibrosis (IF) in two models: hypertension; and chronic renal allograft rejection. To this end, we used spontaneously hypertensive salt-sensitive Dahl (Dahl-S) and CD40 mutant (Dahl-S^CD40mut) rats (both displaying hypertension [sim]180 mm Hg at 6 weeks old). These Dahl-S and Dahl-S^CD40mut rats were examined for IF at 64 days of age or at 90 days post renal transplantation to normotensive Brown Norway (BN) allogeneic recipients. We hypothesize that CD40 signaling regulates IF in both hypertension and chronic allograft rejection. Methods/Results: As previously reported, Dahl-S^CD40mut rats showed significantly less fibrosis and improved kidney function parameters over Dahl-S rats including urinary protein excretion; plasma creatinine; and creatinine clearance on both low (0.3%) and high (2%) salt diets. However, there was no difference in the systolic blood pressure between Dahl-S and Dahl-S^CD40mut rats (181 ± 3.8 vs. 183 ± 4.8 mmHg, NS), suggesting that CD40 regulates IF in hypertension. Signaling experiments in the hypertensive model showed that proximal tubules from Dahl-S^CD40mut rats had a significant reduction in phospho-lyn kinase activity (p=0.05) and expression of PAI-1 (p=0.01) compared to tubules from Dahl-S rats (not shown). Likewise, normotensive BN recipients treated for 30 days with tacrolimus 1.5 mg/kg (to block acute rejection) displayed significantly reduced IF in kidneys from Dahl-S^CD40mut rats in comparison to Dahl-S rats (Fig. 1A). Dahl-S^CD40mut kidney transplants also had reduced collagen 1A1 (COL1A1) and COL3A1 (Fig. 1B) as well as MCP-1 and PI-1 (Fig. 1C) compared to Dahl-S kidney grafts, suggesting inhibition of CD40/PI1/lyn signaling for fibrosis. Conclusion: These data for the first time connect IF with CD40 signaling in proximal tubules in both hypertension and chronic allograft rejection. We propose that direct inhibition of CD40 signaling in kidneys may have a dramatic impact on IF in both hypertension and chronic allograft rejection.

CITATION INFORMATION: Bletsos V., Breidenbach J., Haller S., Stepkowski S. CD40 Signaling in Proximal Tubules Regulates Fibrosis in Both Hypertension and Chronic Allograft Rejection Am J Transplant. 2017;17 (suppl 3).

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