Afkarian Maryam, Hirsch Irl B, Tuttle Katherine R, Greenbaum Carla, Himmelfarb Jonathan, de Boer Ian H
Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.
Physiol Rep. 2014 May 2;2(5):e12010. doi: 10.14814/phy2.12010. Print 2014.
Abstract The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter- and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) μg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) μg/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) μg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) μg/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics.
肾素-血管紧张素系统（RAS）、骨形态发生蛋白（BMP）和WNT信号通路参与糖尿病肾病（DKD）的发病机制。本研究对RAS、BMP和WNT信号通路的组成成分尿血管紧张素原（AGT）、gremlin-1和基质金属蛋白酶7（MMP-7）的检测方法进行了表征，并检测了它们在DKD中的排泄情况。我们测量了1型糖尿病合并DKD（n = 20）、长期（n = 61）或新发（n = 10）1型糖尿病无DKD患者的尿AGT、gremlin-1和MMP-7。还对11例2型DKD患者在坎地沙坦治疗前后的这些尿蛋白进行了定量。所采用的免疫分析方法在分析间、分析内和个体内的变异与用于尿白蛋白的分析方法相当。1型糖尿病合并DKD和未合并DKD患者的尿AGT浓度中位数（IQR）分别为226.0（82.1，550.3）和13.0（7.8，20.0）μg/g肌酐（P < 0.001）。尿gremlin-1浓度中位数（IQR）分别为48.6（14.2，254.1）和3.6（1.7，5.5）μg/g（P < 0.001）。尿MMP-7浓度中位数（IQR）分别为6.0（3.8，10.5）和1.0（0.4，2.9）μg/g肌酐（P < 0.001）。坎地沙坦治疗使尿AGT/肌酐中位数（IQR）从23.5（1.6，105.1）降至2.0（1.4，13.7）μg/g，但未达到统计学意义。坎地沙坦治疗后尿gremlin-1和MMP-7排泄未减少。总之，DKD的特征是尿AGT、MMP-7和gremlin-1显著升高。AGT对RAS抑制有反应而降低，表明该标志物反映治疗反应。RAS、BMP和WNT信号通路的尿成分可能有助于识别DKD风险并促进新型治疗方法的开发。
