Ju Wenjun, Eichinger Felix, Bitzer Markus, Oh Jun, McWeeney Shannon, Berthier Celine C, Shedden Kerby, Cohen Clemens D, Henger Anna, Krick Stefanie, Kopp Jeffrey B, Stoeckert Christian J, Dikman Steven, Schröppel Bernd, Thomas David B, Schlondorff Detlef, Kretzler Matthias, Böttinger Erwin P
Dept. of Medicine, Mount Sinai Medical Center, One Gustave L. Levy Pl., Box 1118, New York, NY 10029, USA.
Am J Pathol. 2009 Jun;174(6):2073-85. doi: 10.2353/ajpath.2009.080888.
Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-beta1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R(2) = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans.
尽管慢性肾脏病（CKD）很常见，但只有一小部分CKD患者会进展至终末期肾病。根据进展风险对CKD人群进行分层的分子预测指标仍未被发现。在此，我们对以肾病进展异质性为特征的转化生长因子-β1转基因（Tg）小鼠的肾脏进行转录谱分析，以鉴定43个基因，这些基因在2周龄动物肾小管间质纤维化发生前，可根据肾小球凋亡的严重程度区分肾脏。在所检测的基因中，19个基因在2周龄单侧肾切除的左肾中的mRNA表达与4周龄Tg小鼠右肾中的肾病严重程度之间存在显著相关性。43个基因的人类直系同源基因在肾活检中的基因表达谱与CKD I至V期患者的估计肾小球滤过率高度显著相关（R² = 0.53；P < 0.001），并区分了CKD I/II期和III/IV/V期组，阳性预测值和阴性预测值分别为0.8和0.83。通过免疫组织化学分别在Tg小鼠的肾脏以及IgA肾病和CKD I至V期患者的肾活检中成功验证了所选基因的蛋白表达模式。总之，我们开发了新的mRNA和蛋白表达特征，可预测小鼠的进行性肾纤维化，可能是人类CKD进展的有用分子预测指标。
