Abstract
Renal ischemia–reperfusion (IR) injury and cyclosporine A (CsA) nephrotoxicity affect allograft function and survival. The prolonged effects and underlying mechanisms of erythropoietin derived cyclic helix B peptide (CHBP) and/or caspase-3 small interfering RNA (CASP-3siRNA) were investigated in mouse kidneys, as well as kidney epithelial cells (TCMK-1), subjected to transplant-related injuries. Bilateral renal pedicles were clamped for 30 min followed by reperfusion for 2 and 8 weeks, with/without 35 mg/kg CsA gavage daily and/or 24 nmol/kg CHBP intraperitoneal injection every 3 days. The ratio of urinary albumin to creatinine was raised by IR injury, further increased by CsA and lowered by CHBP at 2, 4, 6 and 8 weeks, whereas the level of SCr was not significantly affected. Similar change trends were revealed in tubulointerstitial damage and fibrosis, HMGB1 and active CASP-3 protein. Increased apoptotic cells in IR kidneys were decreased by CsA and CHBP at 2 and/or 8 weeks. p70 S6 kinase and mTOR were reduced by CsA with/without CHBP at 2 weeks, so were S6 ribosomal protein and GSK-3β at 8 weeks, with reduced CASP-3 at both time points. CASP-3 was further decreased by CHBP in IR or IR + CsA kidneys at 2 or 8 weeks. Furthermore, in TCMK-1 cells CsA induced apoptosis was decreased by CHBP and/or CASP-3siRNA treatment. Taken together, CHBP predominantly protects kidneys against IR injury at 2 weeks and/or CsA nephrotoxicity at 8 weeks, with different underlying mechanisms. Urinary albumin/creatinine is a good biomarker in monitoring the progression of transplant-related injuries. CsA divergently affects apoptosis in kidneys and cultured kidney epithelial cells, in which CHBP and/or CASP-3siRNA reduces inflammation and apoptosis.
Highlights
Kidney transplantation is the life-changing treatment for patients with end-stage renal disease, whereas chronic allograft dysfunction (CAD) and donor shortage are still major obstacles [1]
The ratio of urinary albumin to creatinine was increased by cyclosporine A (CsA) compared with that produced by IR kidneys at 4 weeks (Figures 1B, C), while this ratio was increased by IR compared with the sham controls at 6 and 8 weeks (Figures 1D, E)
The dynamic profile of urinary albumin/creatinine was higher in the IR group compared with the control and cyclic helix B peptide (CHBP) treated groups, and further increased by CsA at all-time points over 2–8 weeks (Figure 1F)
Summary
Kidney transplantation is the life-changing treatment for patients with end-stage renal disease, whereas chronic allograft dysfunction (CAD) and donor shortage are still major obstacles [1]. Ischemia–reperfusion (IR) injury, unavoidable in organ transplantation, is associated with delayed graft function, acute rejection, and subsequent CAD [2]. IR injury initiates immune responses, oxidative damage, inflammation and cell death, in which tubular epithelial cells (TECs) are most vulnerable [3,4,5]. Survived TECs participate in alleviating injury and promoting repair [6] via dedifferentiating and entering cell cycle within a few hours post injury [7]. Cyclosporine A (CsA) as an immunosuppressant was used after kidney transplantation to reduce acute rejection and early graft losses [8]. CsA has not improved long-term graft survival due to its nephrotoxicity [9], characterized by tubulointerstitial fibrosis and afferent arteriolar hyalinosis [10]
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