Apoptosis and treatment of chronic allograft nephropathy with everolimus

Abstract

Everolimus ameliorates CAN as a result of antiproliferative or apoptosis-enhancing effects.

Expression of the Integrin-Linked Kinase in a Rat Kidney Model of Chronic Allograft Nephropathy

“…Regarding the previous studies of classical CAN in F344/Lewis rat models [2][3][4][5][6], mild focal mononuclear cell infiltration was observed at the 1st week post-transplantation, whereas at the 12th week, the disease was characterized by tubulointerstitial mononuclear cell infiltration and vascular intimal proliferation with proteinuria. The renal function became gradually impaired thereafter.…”

“…Total RNA was extracted from representative kidney samples using Trizol reagent (Gibco/BRL, USA) as previously described [2][3][4][5], and the samples were stored at -80°C until use. In brief, 60-100 mg of frozen tissue sample was homogenized in 1 ml of Trizol reagent, and 200 ll of chloroform was added to the homogenate.…”

“…The early pathological change in CAN is the infiltration of mononuclear cells in renal interstitium and the transmigration and proliferation of vascular smooth muscle cells (SMCs). At the early stage of CAN, first the mild focal mononuclear cells infiltration occurs which increases over time in conjunction with SMC proliferation and migration in vessel walls and breach of the vascular elastic membrane [1][2][3][4][5]. We [6] and others [7][8][9][10][11][12][13] have previously shown that matrix metalloproteinase-9 (MMP-9) plays an important role in the pathogenesis of CAN in correlation with interstitial mononuclear cells infiltration and vascular intimal proliferation.…”

The use of everolimus in renal-transplant patients

“…This attribute may represent an additional benefit of everolimus as these proliferative processes are implicated in the development of CAN in renal-transplant recipients and cardiac allograft vasculopathy in cardiac-transplant recipients, which are key causes of allograft dysfunction 11,12 Furthermore, animal studies have demonstrated that the antiproliferative effects of everolimus reduce long-term graft-specific histological changes, delaying the progression of CAN, even when already at an advanced stage. 13 Studies of sirolimus and everolimus drug-eluting stents further support the ability of this class of drugs to inhibit pathological vascular remodeling. 28,29 Taken together, these data suggest that the mechanism of action of everolimus appears to target the key cause of CAN.…”

“…11,12 Animal studies have demonstrated that the antiproliferative effects of everolimus reduce long-term graft-specific histological changes, delaying the progression of CAN, even when already at an advanced stage. 13 Therefore, the mechanism of action of everolimus appears to target the key cause of CAN.…”