Togashi Yuko, Miyamoto Yohei
Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1, Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Exp Toxicol Pathol. 2013 Jul;65(5):615-22. doi: 10.1016/j.etp.2012.06.005. Epub 2012 Jul 12.
Cystatin C, a cysteine protease inhibitor, is a novel biomarker of renal damage. In the present study, we examined the usefulness of urinary cystatin C for the detection of diabetic nephropathy in Zucker diabetic fatty (ZDF) rats compared to other biomarkers (β2-microglobulin, calbindin, clusterin, epidermal growth factor (EGF), alpha-glutathione S-transferase (GST-α), mu-glutathione S-transferase (GST-μ), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin, tissue inhibitor of metalloprotease-1 (TIMP-1), and vascular endothelial growth factor (VEGF). Urinary levels of cystatin C were increased in ZDF rats where renal damage was not histopathologically observed, and then further increased with the progression of renal damage, demonstrating the usefulness of early detection and accurate assessment of diabetic nephropathy. Urinary β2-microglobulin, clusterin, GST-μ, KIM-1, and osteopontin had the potency to detect renal damage in ZDF rats as well as cystatin C. We also investigated immunohistochemical localization of cystatin C in the kidney according to progressive renal damage. Cystatin C expression was mainly observed in the proximal renal tubule in ZDF rats, and hardly changed with progression of nephropathy. When renal damage was remarkable, cystatin C expression was also observed in the tubular lumen of the cortex and medulla, which was considered to be characteristic of renal damage in diabetic nephropathy. In conclusion, urinary cystatin C, β2-microglobulin, clusterin, GST-μ, KIM-1, and osteopontin could be useful biomarkers of diabetic nephropathy in ZDF rats. Immunohistochemical cystatin C expression in the proximal renal tubule was hardly changed by the progression of diabetic nephropathy, but it was newly observed in the tubular lumen when renal damage was remarkable in ZDF rats.
胱抑素C是一种半胱氨酸蛋白酶抑制剂，是肾损伤的新型生物标志物。在本研究中，我们检测了尿胱抑素C与其他生物标志物（β2-微球蛋白、钙结合蛋白、簇集素、表皮生长因子（EGF）、α-谷胱甘肽S-转移酶（GST-α）、μ-谷胱甘肽S-转移酶（GST-μ）、肾损伤分子-1（KIM-1）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、骨桥蛋白、金属蛋白酶组织抑制剂-1（TIMP-1）和血管内皮生长因子（VEGF））相比，在检测Zucker糖尿病脂肪（ZDF）大鼠糖尿病肾病中的作用。在未观察到组织病理学肾损伤的ZDF大鼠中，尿胱抑素C水平升高，然后随着肾损伤的进展进一步升高，证明其在糖尿病肾病早期检测和准确评估中的作用。尿β2-微球蛋白、簇集素、GST-μ、KIM-1和骨桥蛋白与胱抑素C一样，具有检测ZDF大鼠肾损伤的能力。我们还根据进行性肾损伤研究了胱抑素C在肾脏中的免疫组织化学定位。胱抑素C表达主要在ZDF大鼠的近端肾小管中观察到，并且几乎不随肾病进展而变化。当肾损伤显著时，在皮质和髓质的肾小管腔中也观察到胱抑素C表达，这被认为是糖尿病肾病肾损伤的特征。总之，尿胱抑素C、β2-微球蛋白、簇集素、GST-μ、KIM-1和骨桥蛋白可能是ZDF大鼠糖尿病肾病的有用生物标志物。近端肾小管中胱抑素C的免疫组织化学表达几乎不随糖尿病肾病进展而变化，但在ZDF大鼠肾损伤显著时，在肾小管腔中新观察到该表达。
