Abstract
Objectives Most patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN) with severe kidney manifestations. Renal fibrosis can be primarily attributed to overproliferation of mesangial cells (MCs), which are subject to drug treatment. Nevertheless, the detailed mechanisms remain elusive. We sought to identify the effect of cyclophosphamide (CTX), a drug commonly used for LN treatment, on MC proliferation and explore its underlying mechanisms. Material/Methods. Cell proliferation and fibrosis in mouse kidney tissues were determined by histopathology staining techniques. Flow cytometry was used for cell cycle analysis. Cell cycle regulators were examined in vitro following treatment of immortalized human MCs with platelet-derived growth factor subunit B (PDGF-B). Quantitative real-time PCR and western blot analyses were used to measure the mRNA and protein levels of candidate cell cycle regulators, respectively. Results CTX inhibited cell overproliferation induced by platelet-derived growth factor subunit B in vitro and in vivo. CTX (40 mg/l) was sufficient to induce G0/G1 phase cell cycle arrest. CTX treatment downregulated many critical cell cycle regulators including cyclins and cyclin-dependent kinases but upregulated cyclin-dependent kinase inhibitors. Additionally, CTX-treated samples showed significantly reduced fibrosis, as indicated by lower expression of interleukin-1β and α-smooth muscle actin. Conclusion CTX inhibits proliferation of MCs by modulating cell cycle regulator and therefore arresting them at G1 phase. CTX treatment significantly alleviates the severity of renal fibrosis. These findings provide novel insights into the mechanisms by which CTX affects LN.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation in affected organs attacked by the immune system
To determine the mechanisms by which CTX affects human MCs (HMCs) proliferation, we examined the expression of genes that are known to regulate G1 phase, such as cyclin D1, cyclin E, CDK2, and CDK4 (Figure 4)
We found that expression of the fibrotic protein α-smooth muscle actin (α-SMA) and inflammatory factor IL-1β was markedly reduced in the lupus nephritis (LN) mouse model after treatment with CTX, which delayed the progression of renal fibrosis and inflammation
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation in affected organs attacked by the immune system. Up to 70% SLE patients develop renal involvement, which are clinically diagnosed as lupus nephritis (LN). LN remains a leading cause of disability and death worldwide. Nephrotic syndrome, and even acute nephritis with alternating active and stable phases are commonly seen in LN patients [1, 2]. 1 out 10 SLE patients ends up developing end-stage renal diseases [3, 4], and LN-related renal failure is the major cause of death among patients with SLE. While the clinical characteristics of LN are complex, glomerular injury represents a predominant symptom. Glomerular injuries are histologically classified based on glomerular immune complex deposition and mesangial cell (MC) overproliferation
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