Abstract
Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse extracellular matrix (ECM) crosslinking, were shown to implicate in tissue scarring. It is hypothesized that inhibition of these enzymes may render therapeutic effects against CsA-induced nephropathy. In this study, 6-to-8 weeks old C57BL/6 J mice were administered saline or CsA (30 mg/kg/day s.c) for 16 weeks. At 8 weeks, CsA-treated animals were divided into 5 groups respectively treated with: (1) vehicle, (2) PXS-5505 (Pan-LOX inhibitor), (3) PXS-5382 (LOX-like 2 inhibitor), (4) PXS-5505 for 4 weeks then PXS-5382 for 4 weeks (sequential therapy), and (5) Telmisartan (standard therapy). Our results indicate that CsA administration significantly increased the levels of blood urea nitrogen, glomerular and tubular injury, tubulointerstitial fibrosis, inflammation and oxidative stress in mouse kidney. These changes were associated with upregulated mRNA expression of LOX and LOXL2. Administration of Pan-LOX or LOXL2 inhibitors or the sequential therapy suppressed the expression of ECM proteins (α-SMA, FN and COL1A), matrix metalloproteases (MMP)2 and 9, inflammatory markers (TNFα and MCP-1) and TGF-β1-Smad3 signalling. Among all regimens including telmisartan, only Pan-LOX inhibitor PXS-5505 was able to attenuate uraemia. Collectively, our study suggests that Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy due to CsA administration.
Highlights
Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis
Neither the plasma level of kidney injury marker (KIM)-1 nor the urinary albumin/creatinine ratio (UACR) was elevated in Cyclosporin A (CsA) treated mice compared to other groups
In comparison to the vehicle control, we found that CsA administration significantly upregulated NAPDH oxidase (NOX)[4] mRNA expression (P < 0.01, Fig. 6A), a major source of reactive oxygen species (ROS)[33]
Summary
Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Nephrotoxic side effects and the inherent requirement for monitoring of blood pressure levels have limited the clinical utility of calcineurin inhibitors and led to the development of alternative anti-rejection strategies, including CsA-dose reduction combined with administration of anti-inflammation (e.g. prednisone) and anti-proliferative agents (e.g. mycophenolate mofetil) These treatments can result in insufficient immunosuppression, leading to limited short- and long-term benefits to graft survival and nephrotoxicity[7,8]. Recent studies have shown that LOXL2 inhibition can lead to marked reductions in activated fibroblasts[17,18], reduced collagen content and crosslink formation and reversal of fibrosis in these tissues[19,20,21] It is unclear whether LOX/LOXL2 inhibition is beneficial in attenuating the development of CsA nephrotoxicity. As too much suppression of LOXs can affect healthy ECM turnover, the idea of the sequential approach is to inhibit all LOX isoforms at the initial phase of fibrosis formation, switch to a more specific, moderate inhibitor to maintain a certain level of ECM that is necessary for systemic scarring/healing p rocesses[22]
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