Complement factor B inhibitor LNP023 improves lupus nephritis in MRL/lpr mice

Chen, Keng; Deng, Yiyao; Shang, Shunlai; Tang, Lifeng; Li, Qinggang; Bai, Xueyuan; Chen, Xiangmei

doi:10.1016/j.biopha.2022.113433

Cited by 14 publications

(6 citation statements)

References 29 publications

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“…Compared with the MRL/LPR group, the LNP023 group showed reduced lupus-like symptoms, improved renal function, and reduced C3 deposition in the serum, renal tissues, and liver tissues. Moreover, LNP023 alleviated pathological damage in the kidneys of MRL/LPR mice (Chen et al 2022 ). In the present study, it was confirmed that C3 levels were significantly increased in mice with lupus nephritis, which was dramatically repressed by the knockdown of HE4, indicating that a regulatory relationship might exist between HE4 and C3.…”

Section: Discussionmentioning

confidence: 99%

Silencing HE4 alleviates the renal fibrosis in lupus nephritis mice by regulating the C3/MMPs/prss axis

Li,

Zhong,

Yang

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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To explore the regulatory effect of human epididymis protein 4 (HE4) on renal fibrosis in mice with lupus nephritis (LN) and the underlying mechanism. Ten-week old MRL/LPR mice were injected with HE4 shRNA adenovirus vector through the renal pelvis for 5 days. Renal tissues were extracted for HE and Masson staining to evaluate pathological changes and fibrosis in lupus nephritis mice. The level of urine protein was measured using a biochemical analyzer, while the expression level of HE4 and p-NF-κB p65 in renal tissues was visualized using an immunofluorescence assay. The level of β2-microglobulin (β2-MG), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (Kim-1) was determined by the immunohistochemical assay. Western blotting was used to determine the levels of C3, HE4, matrix metalloproteinase-2 (MMP2), MMP9, p-p65, prss23, and prss35 in renal tissues. Compared to wild-type C57BL/6 mice, MRL/LPR mice showed a marked increase in the number of glomeruli, hyperplasic basement membrane, severe infiltration of inflammatory cells in renal tubules and glomeruli, obvious necrosis in glomeruli, elevated fibrosis levels, and increased levels of urine protein, β2-MG, NGAL, Kim-1, C3, HE4, MMP2, MMP9, and p-p65; and decreased levels of prss23 and prss35 were observed in MRL/LPR mice. After the administration of the HE4 shRNA adenovirus vector, the repaired structure of renal tubules and glomeruli improved infiltration of inflammatory cells, reduced collagen fiber and urine protein, suppressed levels of C3, HE4, MMP2, MMP9, and p-P65, and facilitated the expression of prss23 and prss35 which were observed. Silencing HE4 improved renal fibrosis and inhibited inflammation in mice with lupus nephritis, which may play a role in inhibiting C3/MMPs and promoting prss-related protein expression.

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Section: Discussionmentioning

confidence: 99%

Silencing HE4 alleviates the renal fibrosis in lupus nephritis mice by regulating the C3/MMPs/prss axis

Li,

Zhong,

Yang

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Results from a clinical trial showed that it significantly improved remission and survival rate in patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy (NCT047906), but its efficacy and safety in LN are still being tested (NCT02682407). LNP023, an invertible binding inhibitor of CFB, could alleviate pathological injury in the kidneys of MRL/lpr mice ( 56 ). In addition, CFB cleavage is abrogated in aHUS (atypical hemolytic uremic syndrome) patients’ serum when using danicopan, which is an oral CFD inhibitor ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Thrombotic microangiopathy mediates poor prognosis among lupus nephritis via complement lectin and alternative pathway activation

Zhang

Xing

2022

Front. Immunol.

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ObjectiveThe pathogenesis of thrombotic microangiopathy (TMA) in lupus nephritis (LN) remains complicated. This study aimed to detect the deposition of complement lectin pathway (LP) and alternative pathway (AP) components in renal tissues, then evaluate the clinicopathological characteristics and risk factors for renal survival between patients with or without TMA in LN cohorts.MethodsWe included 79 patients with biopsy-proven LN-associated TMA and matched the same number of LN patients without TMA as the control group. The deposition of mannose binding lectin (MBL), MBL-associated serine proteases 1/3 (MASP1/3), complement factor B (CFB), complement factor D (CFD), C4d, and von Willebrand factor (VWF) in renal tissue was assessed by immunohistochemistry and immunofluorescence. Besides, co-localization of C5b-9 and CD34 was detected by confocal microscopy.ResultsIn our retrospective cohort, the incidence of acute kidney injury (30% vs. 14%, p = 0.013), acute hemodialysis (35% vs. 5%, p < 0.001), and interstitial fibrosis (43% vs. 13%, p < 0.001) is higher in the TMA, compared with the control group. Despite aggressive steroids pulse, plasma exchange, and immunosuppressive therapy among TMA group, they still had significantly inferior 3-year renal survival rates (68% vs. 89%, p = 0.002) than those in the non-TMA group. COX regression analysis identified that TMA (HR 4.807, 95% CI [2.052, 11.263], p < 0.001) is a risk factor in LN. MBL, MASP1/3, CFB, CFD, C4d, and VWF deposited along the glomerulus among LN, while TMA had stronger staining intensity and deposition. The co-localized expression of CD34 and C5b-9 in the endothelial cells was also observed in the renal tissues.ConclusionsTMA is an independent risk factor for renal survival in LN patients. Moreover, LP and AP activation are involved in the pathogenesis of LN-associated TMA.

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“…Table 6 summarizes the presumable applications of ncRNAs (miRs, lncRNAs and circRNAs) as novel potential therapeutic strategies for LN in the future. • IFN-γ-induced JAK/STAT signaling and CXCL10 expression [167] II Modulation of complement levels [169] or complement factor B level [170] III Targeting proinflammatory cytokines or growth factors by microRNAs…”

Section: Molecular Mechanisms For Other Unique Ncrna Inhibitors In Th...mentioning

confidence: 99%

“…These results indicated that C1q ameliorated inflammation and macrophage infiltration, as well as mesangial proliferation by inhibiting the NK-κB pathway in renal tissues. Because the abnormal activation of the alternative complement pathway is involved in LN pathogenesis, Chen et al [ 170 ] used the complement factor B, LNP023, to treat MRL/ lpr mice and evaluated its effectiveness. They found that the treatment not only improved the symptoms/signs, but also regulated the activation of TNF-α, STAT3, PI3K-Akt, HIF, and Erb-B signaling pathways.…”

Section: Potential Novel Therapeutic Strategy For Ln In Futurementioning

confidence: 99%

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis

Tsai

Shen

et al. 2023

IJMS

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Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA–anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.

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Complement factor B inhibitor LNP023 improves lupus nephritis in MRL/lpr mice

Cited by 14 publications

References 29 publications

Silencing HE4 alleviates the renal fibrosis in lupus nephritis mice by regulating the C3/MMPs/prss axis

Silencing HE4 alleviates the renal fibrosis in lupus nephritis mice by regulating the C3/MMPs/prss axis

Thrombotic microangiopathy mediates poor prognosis among lupus nephritis via complement lectin and alternative pathway activation

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis

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