Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin.
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.
Loverre
Antonia
A
Department of Nephrology, University of Foggia, Italy.
Ditonno
Pasquale
P
Crovace
Antonio
A
Gesualdo
Loreto
L
Ranieri
Elena
E
Pontrelli
Paola
P
Stallone
Giovanni
G
Infante
Barbara
B
Schena
Antonio
A
Di Paolo
Salvatore
S
Capobianco
Carmen
C
Ursi
Michele
M
Palazzo
Silvano
S
Battaglia
Michele
M
Selvaggi
Francesco Paolo
FP
Schena
Francesco Paolo
FP
Grandaliano
Giuseppe
G
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011336:Probability; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000187:drug effects; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D012307:Risk Factors; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D000097782:NF-kappaB-Inducing Kinase
D007166:Immunosuppressive Agents; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D000097782:NF-kappaB-Inducing Kinase