Ramya T Kolli, Sameera Chathuranga Gunasekara, Matthew W Foster, Sitaramaraju Adduri, Anna Strasma, Christina Wyatt, Nagarjun V Konduru, Mangala C S De Silva, Nishad Jayasundara
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As expected, renal tubular injury in patients with CKDu was evinced by increases in albumin, cystatin C, and β<sub>2</sub>-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-<i>N</i>-acetylglucosaminidase, were decreased in patients with CKDu. Furthermore, urinary excretion of aquaporins found higher in CKD was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, the CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Furthermore, we report a decrease in endocytic receptor proteins responsible for protein reabsorption (megalin and cubilin) that correlated with an increase in abundance of 15 of their cognate ligands. Functional pathway analyses identified kidney-specific differentially abundant proteins in patients with CKDu denoted significant changes in the complement cascade and coagulation systems, cell death, lysosomal function, and metabolic pathways. Overall, our findings provide potential early detection markers to diagnose and distinguish CKDu and warrant further analyses on the role of lysosomal, mitochondrial, and protein reabsorption processes and their link to the complement system and lipid metabolism in CKDu onset and progression.<b>NEW & NOTEWORTHY</b> CKDu is a global health concern debilitating a number of tropical rural farming communities. In the absence of typical risk factors like diabetes and hypertension and the lack of molecular markers, it is crucial to identify potential early disease markers. Here, we detail the first urinary proteome profile to distinguish CKDu from CKD. 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CKDu is not associated with typical risk factors (e.g., diabetes) and strongly correlates with environmental drivers. To gain potential insights into disease etiology and diagnosis, here we report the first urinary proteome comparing patients with CKDu and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins. In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in patients with CKDu was evinced by increases in albumin, cystatin C, and β<sub>2</sub>-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-<i>N</i>-acetylglucosaminidase, were decreased in patients with CKDu. Furthermore, urinary excretion of aquaporins found higher in CKD was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, the CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. 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引用次数: 2
摘要
病因不明的慢性肾脏疾病(CKD)是影响热带农业社区的全球性健康问题。CKDu与典型危险因素(如糖尿病)无关,与环境驱动因素密切相关。为了获得对疾病病因和诊断的潜在见解,本文首次报道了比较斯里兰卡CKDu患者和非CKDu对照患者的尿蛋白质组学。我们发现了944种差异丰富的蛋白质。计算机分析鉴定出636种可能来自肾脏和泌尿生殖系统的蛋白质。正如预期的那样,CKDu患者的肾小管损伤表现为白蛋白、胱抑素C和β2微球蛋白的增加。然而,一些在CKD下通常升高的蛋白,包括骨桥蛋白和α- n -乙酰氨基葡萄糖酶,在CKDu患者中降低。此外,CKD患者尿中水通道蛋白的排泄量较高,CKDu患者尿中水通道蛋白的排泄量较低。与先前CKD尿蛋白质组数据集的比较揭示了CKDu的独特蛋白质组。值得注意的是,CKDu尿蛋白质组与线粒体疾病患者的尿蛋白质组相对相似。此外,我们报告了负责蛋白质重吸收的内吞受体蛋白(meggalin和cubilin)的减少,这与它们的15种同源配体的丰度增加有关。功能途径分析发现,CKDu患者肾脏特异性差异丰富的蛋白质表明补体级联和凝血系统、细胞死亡、溶酶体功能和代谢途径发生了显著变化。总的来说,我们的研究结果为诊断和区分CKDu提供了潜在的早期检测标记,并为进一步分析溶酶体、线粒体和蛋白质重吸收过程的作用以及它们与补体系统和脂质代谢在CKDu发病和进展中的联系提供了依据。CKDu是一种全球性的健康问题,使许多热带农村农业社区衰弱。在缺乏糖尿病和高血压等典型危险因素和缺乏分子标志物的情况下,识别潜在的早期疾病标志物至关重要。在这里,我们详细介绍了第一个泌尿蛋白质组谱来区分CKDu和CKD。我们的数据和计算机通路分析推断了线粒体、溶酶体和蛋白质重吸收过程在疾病发生和进展中的作用。
The urinary proteome infers dysregulation of mitochondrial, lysosomal, and protein reabsorption processes in chronic kidney disease of unknown etiology (CKDu).
Chronic kidney disease (CKD) of uncertain etiology (CKDu) is a global health concern affecting tropical farming communities. CKDu is not associated with typical risk factors (e.g., diabetes) and strongly correlates with environmental drivers. To gain potential insights into disease etiology and diagnosis, here we report the first urinary proteome comparing patients with CKDu and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins. In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in patients with CKDu was evinced by increases in albumin, cystatin C, and β2-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-N-acetylglucosaminidase, were decreased in patients with CKDu. Furthermore, urinary excretion of aquaporins found higher in CKD was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, the CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Furthermore, we report a decrease in endocytic receptor proteins responsible for protein reabsorption (megalin and cubilin) that correlated with an increase in abundance of 15 of their cognate ligands. Functional pathway analyses identified kidney-specific differentially abundant proteins in patients with CKDu denoted significant changes in the complement cascade and coagulation systems, cell death, lysosomal function, and metabolic pathways. Overall, our findings provide potential early detection markers to diagnose and distinguish CKDu and warrant further analyses on the role of lysosomal, mitochondrial, and protein reabsorption processes and their link to the complement system and lipid metabolism in CKDu onset and progression.NEW & NOTEWORTHY CKDu is a global health concern debilitating a number of tropical rural farming communities. In the absence of typical risk factors like diabetes and hypertension and the lack of molecular markers, it is crucial to identify potential early disease markers. Here, we detail the first urinary proteome profile to distinguish CKDu from CKD. Our data and in silico pathway analyses infer the roles of mitochondrial, lysosomal, and protein reabsorption processes in disease onset and progression.
期刊介绍:
The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.