Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor‑κB signaling pathway in lupus nephritis mice

Abstract

Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus, leading to permanent renal damage and chronic kidney disease. Hydroxychloroquine (HCQ) serves a protective role against lupus-associated clinical manifestations and medical complications; however, it results in numerous adverse reactions, limiting its long-term use. The aim of the present study was to investigate the combined effect of HCQ and artemisinin (ART) on LN, and to elucidate the underlying mechanisms. An in vivo LN mouse model was prepared, and the animals were administered prednisone (PDS; serving as a positive control), high-dose HCQ (H-HCQ) or low-dose HCQ combined with ART (L-HCQ + ART) once daily for 8 weeks. The body weight, serum biochemical parameters, immune and inflammatory indicators, renal and spleen histological alterations, and mRNA expression levels of Kruppel-like factor 15 (KLF15) and nuclear factor-κB (NF-κB) were analyzed. It was observed that L-HCQ + ART and H-HCQ ameliorated the LN-induced body weight decrease, and significantly decreased the levels of anti-double stranded DNA, antinuclear antibodies, immunoglobulin G, interferon γ, tumor necrosis factor-α and transforming growth factor-β1, as well as improved the kidney and spleen pathology, when compared with the model group. In addition, L-HCQ + ART and H-HCQ treatments induced KLF15 upregulation and NF-κB downregulation. These results indicated that treatment with L-HCQ + ART exerted renoprotective effects by regulating the expression levels of cytokines, KLF15 and NF-κB. This combination treatment may have a similar immunosuppressive effect as PDS and H-HCQ, and may be a promising alternative for LN treatment.

The Role and Therapeutic Potential of NF-kappa-B Pathway in Severe COVID-19 Patients

“…Hydroxychloroquine, which was initially touted as the wonder drug and used in many regimens for the treatment of COVID-19, has fallen off from popularity due to its cardiac toxicity. It reduces the levels of TNF-α, TNF-1β, IgG and IFN-γ, which in turn blocks the NF-κB pathway (Liang et al 2018 ). Inhaled nitric oxide (NO) may be useful in the management of COVID-19 ARDS, and there is growing evidence that it reduces the inflammatory cell-mediated lung injury by inhibiting neutrophil activation and subsequent pro-inflammatory cytokines.…”

The Therapeutic Effect of Artemisinin and Its Derivatives in Kidney Disease

“…For LN mice, it has been reported that treatment with ARSs could decrease interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6) in serum, and blocked intercellular adhesion molecule-1 (ICAM-1), fractalkine, NF-kB signaling pathway in renal (Dong et al, 2003;Li et al, 2006;Wang et al, 2010;You et al, 2014;Liang et al, 2018). A similar effect was observed in the nephritis and septic AKI models Wan and Li, 2017;Liu et al, 2019).…”

Krüppel-like Factor 15: A Potential Therapeutic Target For Kidney Disease

“…Previous studies have shown that KLF15 can block the interaction of nuclear factor NF-κB p56 with the co-activator P300 by directly interacting with P300, and subsequently by inhibiting the P300-p56-activated inflammatory pathway 42. The most recent evidence has indicated that KLF15 can improve LN 21. A combined treatment of Hydroxychloroquine and artemisinin in LN may exert renal-protective effects by increasing expression levels of KLF15, leading to a decrease in the levels of its downstream target, NF-κB, and consequently suppressing the inflammatory response 21.…”

“…Moreover, KLF15 was also involved in metabolic dysfunctions, including diabetes, inflammation, obesity, and cardiac hypertrophy 17-20. Recently, a growing number of studies have indicated that KLF15 is implicated in renal physiological processes and pathologic progression of CKD, involving podocyte differentiation, tubular physiology, mesangial pathology, and renal fibrosis 12, 13, 16, 21. An improved understanding of CKD and its molecular mechanisms will enable further research into new therapeutic targets.…”