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Ischemia-Reperfusion Induces Glomerular and Tubular Activation of Proinflammatory and Antiapoptotic Pathways: Differential Modulation by Rapamycin

Antonia Loverre^*, Pasquale Ditonno, Antonio Crovace, Loreto Gesualdo^*, Elena Ranieri, Paola Pontrelli, Giovanni Stallone, Barbara Infante, Antonio Schena, Salvatore Di Paolo, Carmen Capobianco, Michele Ursi, Silvano Palazzo, Michele Battaglia, Francesco Paolo Selvaggi, Francesco Paolo Schena and Giuseppe Grandaliano

*Department of Nephrology, University of Foggia, Foggia, Italy; and Divisions of Urology, Veterinary Surgery, and Nephrology, Department of Emergency and Transplantation, University of Bari, Bari, Italy

Correspondence to Dr. Giuseppe Grandaliano, Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. Phone: +39-080-5592787; Fax: +39-080-5593227; E-mail: g.grandaliano{at}nephro.uniba.it

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt–mammalian target of rapamycin–S6k and NF-B–inducing kinase (NIK)–NF-B axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-B axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK–NF-B pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673