PDF(Pubmed)
Abstract：
UNASSIGNED: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear.
UNASSIGNED: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning.
UNASSIGNED: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS.
UNASSIGNED: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients\' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.
UNASSIGNED: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning.
UNASSIGNED: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS.
UNASSIGNED: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients\' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.
摘要：
■IgA肾病（IgAN），一种全球普遍的肾小球肾炎，表现出复杂的发病机制。组织蛋白酶,溶酶体内的半胱氨酸蛋白酶，涉及各种生理和病理过程，包括肾脏疾病。先前的观察性研究表明，组织蛋白酶和IgAN之间存在潜在的联系，然而确切的因果关系尚不清楚.
■我们使用公开可用的遗传数据进行了全面的双向和多变量孟德尔随机化（MR）研究，以系统地探索组织蛋白酶和IgAN之间的因果关系。此外,采用免疫组织化学（IHC）染色和酶联免疫吸附试验（ELISA）评估IgAN患者肾组织和血清中组织蛋白酶的表达水平。我们通过基因集变异分析(GSVA)研究了潜在的机制，基因集富集分析(GSEA)，和免疫细胞浸润分析。还进行了分子对接和虚拟筛选以通过药物重新定位来鉴定潜在的候选药物。
■单变量MR分析显示组织蛋白酶S(CTSS)水平升高与IgAN风险升高之间存在显著关联。这通过使用逆方差加权（IVW）方法估计的1.041（95％CI=1.009-1.073，P=0.012）的比值比（OR）得到证明。在多变量MR分析中，即使在调整了其他组织蛋白酶之后，CTSS水平升高继续显示与IgAN风险增加密切相关(IVWP=0.020,OR=1.037,95%CI=1.006~1.069).然而,反向MR分析未确定IgAN与各种组织蛋白酶之间的因果关系.IHC和ELISA结果显示，与对照组相比，IgAN患者的肾组织和血清中CTSS显著过表达，与其他一些原发性肾脏疾病如膜性肾病相比，这种高表达是IgAN特有的，微小病变和局灶节段肾小球硬化。免疫细胞浸润的调查，GSEA,和GSVA强调了CTSS表达在IgAN中观察到的免疫失调中的作用。分子对接和虚拟筛选精确定位甲磺酸Camostat，c-Kit-IN-1和Mocetinostat是靶向CTSS的首选药物。
■CTSS水平升高与IgAN风险增加相关，该酶在IgAN患者血清和肾组织中明显过表达。CTSS可能作为诊断生物标志物，为诊断和治疗IgAN提供了新的途径。
■我们使用公开可用的遗传数据进行了全面的双向和多变量孟德尔随机化（MR）研究，以系统地探索组织蛋白酶和IgAN之间的因果关系。此外,采用免疫组织化学（IHC）染色和酶联免疫吸附试验（ELISA）评估IgAN患者肾组织和血清中组织蛋白酶的表达水平。我们通过基因集变异分析(GSVA)研究了潜在的机制，基因集富集分析(GSEA)，和免疫细胞浸润分析。还进行了分子对接和虚拟筛选以通过药物重新定位来鉴定潜在的候选药物。
■单变量MR分析显示组织蛋白酶S(CTSS)水平升高与IgAN风险升高之间存在显著关联。这通过使用逆方差加权（IVW）方法估计的1.041（95％CI=1.009-1.073，P=0.012）的比值比（OR）得到证明。在多变量MR分析中，即使在调整了其他组织蛋白酶之后，CTSS水平升高继续显示与IgAN风险增加密切相关(IVWP=0.020,OR=1.037,95%CI=1.006~1.069).然而,反向MR分析未确定IgAN与各种组织蛋白酶之间的因果关系.IHC和ELISA结果显示，与对照组相比，IgAN患者的肾组织和血清中CTSS显著过表达，与其他一些原发性肾脏疾病如膜性肾病相比，这种高表达是IgAN特有的，微小病变和局灶节段肾小球硬化。免疫细胞浸润的调查，GSEA,和GSVA强调了CTSS表达在IgAN中观察到的免疫失调中的作用。分子对接和虚拟筛选精确定位甲磺酸Camostat，c-Kit-IN-1和Mocetinostat是靶向CTSS的首选药物。
■CTSS水平升高与IgAN风险增加相关，该酶在IgAN患者血清和肾组织中明显过表达。CTSS可能作为诊断生物标志物，为诊断和治疗IgAN提供了新的途径。
