ABSTRACT
Ischemia and subsequent reperfusion (I/R) damage kidney tubular cells and consequently impair renal function. Rabbit bone marrow mesenchymal stem cells (BM-MSCs) expressing human bone morphogenic protein-7 (hBMP-7) regenerated tubular cells and improved renal function in a kidney I/R model. Rabbits were injected immediately after I/R with one of the following: (i) hBMP-7-transduced BM-MSCs (BM-MSCshBMP-7); (ii) enhanced green fluorescent protein-transduced BM-MSCs (BM-MSCsEGFP); or (iii) PBS. The activity of superoxide dismutase (SOD) was higher, and the amount of malondialdehyde (MDA) was lower in the BM-MSCshBMP-7 group than in the BM-MSCsEGFP group. Both the BM-MSCshBMP-7 group and the BM-MSCsEGFP group had higher SOD activity and lower amounts of MDA than the PBS group. Bcl-2- and Bcl-2-associated X protein levels, and other variables, indicated the regeneration of the kidney in both experimental groups. However, the BM-MSCs (hBMP-7) group showed higher activity than the BM-MSCsEGFP group, indicating that the combined strategy of BM-MSC transplantation with hBMP-7 gene therapy could be a useful approach for the treatment of renal IRI.
Subject(s)
Bone Marrow Cells/metabolism , Bone Morphogenetic Protein 7/metabolism , Kidney/metabolism , Mesenchymal Stem Cells/metabolism , Reperfusion Injury/metabolism , Animals , Cell Proliferation , Cells, Cultured , Gene Expression , Humans , Kidney/pathology , Kidney/physiopathology , Malondialdehyde/metabolism , Mesenchymal Stem Cell Transplantation , Rabbits , Reperfusion Injury/genetics , Reperfusion Injury/pathology , Superoxide Dismutase/metabolismABSTRACT
<p><b>OBJECTIVE</b>To investigate the effects of losartan, a specific angiotensin II receptor blocker, on slowing progression of renal insufficiency in patients with biopsy-proven chronic allograft nephropathy (CAN) and the molecular mechanism of the therapy.</p><p><b>METHODS</b>Twenty-two renal transplant recipients with biopsy-proven CAN (group A) were treated with losartan within two months after renal dysfunction for at least one year. Losartan was administered at a dose of 50 mg/d. Twenty-four recipients in the same fashion (group B) who never received angiotensin II receptor antagonist were studied as control. The investigation time for each patient lasted one year. Renal functions and concentrations of plasma and urine transforming growth factor-beta1 (TGF-beta1) were compared between the two groups at the initiation and end of the study. In group A, expressions of TGF-betal mRNA and immunofluorescence intensity of TGF-betal protein and pathological alterations in renal biopsy specimens were compared between before losartan therapy and after one year of the therapy.</p><p><b>RESULTS</b>At the initiation of the investigation, no significant differences were found between group A and group B in clinical data such as donor age, cold-ischemia time, HLA mismatch, levels of creatinine clearance (Ccr), plasma and urine TGF-beta1 concentrations. One year later, 14 of 22 (63.6%) patients showed stable or improved graft functions in group A, and 4 of 24 (16.7%) in group B. The difference was significant (P < 0.05). At the end of the study, urine TGF-betal concentration was 273.8 +/- 84.1 pg/mg x Cr in group A and 457.2 +/- 78.9 pg/mg x Cr in group B. During one year study period, loss of Ccr was 6.6 +/- 5.4 mL/min in group A and 16.2 +/- 9.1 mL/min in group B. Both of the differences were significant between the two groups (P < 0.01). No significant differences were found in plasma TGF-betal concentrations between the four values determined at the initiation and end of the study in the two groups (F = 2.56, P > 0.05). After one year losartan therapy, group A showed a significant decrease in expressions of TGF-beta1 mRNA and TGF-betal protein in renal biopsy specimens [from 1.59 +/- 0.35 to 0.96 +/- 0.27 and from (10.83 +/- 2.33) x l0(6) to (6.41 +/- 1.53) x 10(6), respectively; both P < 0.01], but in light microscopy the histological changes were similar to the first renal biopsy. Losartan was excellently tolerated in all patients in group A. No cases with losartan therapy showed too low blood pressure and other side effects.</p><p><b>CONCLUSION</b>This study suggests that losartan have an effect on slowing progression of CAN. Reducing production of intrarenal TGF-betal may play a decisive role in the efficacy of losartan.</p>
