Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
Sichuan Clinical Research Center for Nephrology, Luzhou 646000, Sichuan, China.
Mol Pharm. 2023 May 1;20(5):2714-2725. doi: 10.1021/acs.molpharmaceut.3c00163. Epub 2023 Apr 3.
Renal fibrosis is the most common pathological feature and common pathway of progression in chronic kidney disease (CKD). We evaluated [Ga]Ga-FAPI-04 small animal positron emission tomography/computed tomography (PET/CT) and biomarkers as noninvasive assessments of renal fibrosis (RF) in CKD rats to generate new ideas for clinical diagnosis. A rat model of renal fibrosis was administered adenine by gavage ( = 28), and the control group was given 0.9% NaCl by gavage ( = 20). At different time points (weeks 1, 2, 4, and 6), five rats were randomly selected from the two groups for [Ga]Ga-FAPI-04 small animal PET/CT imaging. At the same time, the expression of Fibroblast activation protein (FAP) in renal tissue and the expression levels of type III procollagen N-terminal peptide (PIIINP), transforming growth factor (TGF-β1), Klotho, and sex-determining region Y-box protein 9 (SOX9) in blood and urine were determined. FAP was highly expressed in the renal tissue of rats in the CKD group and expression increased with the progression of renal fibrosis. [Ga]Ga-FAPI-04 small animal PET/CT examination showed that the uptake of radioactive tracers in the CKD group was higher than that in the control group, and SUVmax ( = 0.9405) and target-to-background ratio (TBR) ( = 0.9392) were positively correlated with renal fibrosis. The serum levels of PIIINP, TGF-β1, and SOX9 in CKD rats were significantly higher than those in the control group and were positively correlated with RF ( = 0.8234, = 0.7733, and = 0.7135, respectively) and SUVmax ( = 0.8412, = 0.7763, and = 0.6814, respectively). Compared with the control group, the level of serum Klotho decreased and was negatively correlated with RF ( = -0.6925) and SUVmax ( = -0.6322). Compared with the control group, the levels of PIIINP and TGF-β1 in urine were positively correlated with RF ( = 0.8127 and = 0.8077, respectively) and SUVmax ( = 0.8400 and = 0.8177, respectively). Urine Klotho decreased compared with the control group and was negatively correlated with RF ( = -0.5919) and SUVmax ( = -0.5995). The change in urine SOX9 was not statistically significant. In conclusion, compared with renal biopsy, [Ga]Ga-FAPI-04 small animal PET/CT shows renal fibrosis quickly and noninvasively. PIIINP, TGF-β1, and Klotho in serum and urine may be used as biomarkers of RF, and serum SOX9 is expected to become a new diagnostic biomarker of RF.
肾脏纤维化是慢性肾脏病（CKD）最常见的病理特征和共同的进展途径。我们评估了[Ga]Ga-FAPI-04 小动物正电子发射断层扫描/计算机断层扫描（PET/CT）和生物标志物作为 CKD 大鼠肾脏纤维化（RF）的非侵入性评估，为临床诊断提供新的思路。通过灌胃给予肾脏纤维化大鼠腺嘌呤（n = 28），对照组给予 0.9%NaCl 灌胃（n = 20）。在不同时间点（第 1、2、4 和 6 周），从两组中随机选择五只大鼠进行[Ga]Ga-FAPI-04 小动物 PET/CT 成像。同时，检测肾组织中成纤维细胞激活蛋白（FAP）的表达以及血、尿中 III 型前胶原 N 端肽（PIIINP）、转化生长因子（TGF-β1）、Klotho 和性别决定区 Y 框蛋白 9（SOX9）的表达水平。CKD 组大鼠肾组织中 FAP 高表达，且随着肾纤维化的进展表达增加。[Ga]Ga-FAPI-04 小动物 PET/CT 检查显示 CKD 组放射性示踪剂摄取高于对照组，SUVmax（=0.9405）和靶标与背景比（TBR）（=0.9392）与 RF 呈正相关。CKD 大鼠血清 PIIINP、TGF-β1 和 SOX9 水平明显高于对照组，与 RF（=0.8234、=0.7733 和=0.7135）和 SUVmax（=0.8412、=0.7763 和=0.6814）呈正相关。与对照组相比，血清 Klotho 水平降低，与 RF（= -0.6925）和 SUVmax（= -0.6322）呈负相关。与对照组相比，尿中 PIIINP 和 TGF-β1 水平与 RF（=0.8127 和=0.8077）和 SUVmax（=0.8400 和=0.8177）呈正相关。与对照组相比，尿 Klotho 水平降低，与 RF（= -0.5919）和 SUVmax（= -0.5995）呈负相关。尿 SOX9 的变化无统计学意义。总之，与肾活检相比，[Ga]Ga-FAPI-04 小动物 PET/CT 可快速无创地显示肾脏纤维化。血清和尿液中的 PIIINP、TGF-β1 和 Klotho 可能成为 RF 的生物标志物，血清 SOX9 有望成为 RF 的新诊断生物标志物。
