Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: Differential modulation by rapamycin

• Published in: Journal of the American Society of Nephrology 2004-10, Vol.15 (10), p.2675-2686
• Main Authors: LOVERRE, Antonia, DITONNO, Pasquale, CAPOBIANCO, Carmen, URSI, Michele, PALAZZO, Silvano, BATTAGLIA, Michele, SELVAGGI, Francesco Paolo, SCHENA, Francesco Paolo, GRANDALIANO, Giuseppe, CROVACE, Antonio, GESUALDO, Loreto, RANIERI, Elena, PONTRELLI, Paola, STALLONE, Giovanni, INFANTE, Barbara, SCHENA, Antonio, DI PAOLO, Salvatore
• Format: Article
• Language: English
• Subjects: Adult; Animals; Apoptosis - drug effects; Biological and medical sciences; Biopsy, Needle; Disease Models, Animal; Female; Graft Rejection - prevention & control; Humans; Immunohistochemistry; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Kidney Glomerulus - drug effects; Kidney Glomerulus - pathology; Kidney Transplantation - immunology; Kidney Tubules - drug effects; Kidney Tubules - pathology; Male; MAP Kinase Signaling System; Medical sciences; Microscopy, Confocal; Middle Aged; Nephrology. Urinary tract diseases; NF-kappaB-Inducing Kinase; Phosphorylation - drug effects; Probability; Prospective Studies; Protein Serine-Threonine Kinases - analysis; Protein Serine-Threonine Kinases - drug effects; Reference Values; Reperfusion Injury - drug therapy; Reperfusion Injury - immunology; Reperfusion Injury - pathology; Risk Factors; Sirolimus - pharmacology; Sirolimus - therapeutic use; Swine
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1097/01.ASN.0000139932.00971.E4

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-kappaB-inducing kinase (NIK)-NF-kappaB 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-kappaB 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-kappaB 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.