端粒缺陷相关因子和人类IgA肾病的关系

研究目的：分析在中国人群中，端粒缩短以及相关衰老因子与人类IgA肾病发生进展的关系。创新要点：目前的研究发现，端粒功能缺陷是限制分裂增殖、细胞衰老的重要分子机制。它不仅仅与衰老相关，而且在疾病的发生、进展过程中都有直接影响。肾脏的正常衰老过程伴随端粒逐渐缩短，端粒功能缺陷可以加速慢性肾脏疾病进程，并伴随相关衰老因子cathelin相关抗菌肽（CRAMP）、延长因子-1α（EF-1α）、几丁质酶（chitinase）和微管不稳定蛋白（stathmin）等表达增加。本项研究首次在中国人群中，揭示端粒缩短以及相关衰老因子与人类IgA肾病发生进展的关系。研究方法：采用双盲法，以IgA肾病患者（n=177）为实验组，以狼疮肾炎（n=50）、糖尿病肾病（n=30）和局灶节段性肾小球硬化（n=30）病人以及健康人（n=83）为对照组，通过定量荧光原位杂交（qFISH）检测了肾脏组织的端粒长度，并通过酶联免疫吸附试验（ELISA）检测了血液、尿液中的CRAMP、EF-1α、stathrnin的含量，运用几丁质酶试剂盒（CS1030）检测了血液、尿液中几丁质酶的酶活性，运用免疫荧光染色检测了组织中CRAMP的表达情况。重要结论：端粒缩短和相关炎症蛋白与IgA肾病的发生发展有关，并为IgA肾病的特异性诊断和及预后评估提供可靠的研究基础。

Proteins induced by telomere dysfunction are associated with human IgA nephropathy

Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers （cathelin-related antimicrobial peptide （CRAMP）, stathmin, elongation factor-1α （EF-1α）, and chitinase） were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy （IgAN） progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay （ELISA） and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus （SLE）, diabetic nephropathy （DN）, and focal segmental glomerulosclerosis （FSGS）, there is no protein upregulaUon with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% （plasma） and 74.3%/84.2% （urine） sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study.