Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan.
Sci Rep. 2018 Jan 8;8(1):16. doi: 10.1038/s41598-017-18314-w.
(Pro)renin receptor [(P)RR] is expressed in the kidney and is involved in renal injury. Although (P)RR is activated by indoxyl sulfate (IS) and may be related to renal injury, the details remain unclear. We used mouse mesangial cell line SV40 MES13 to investigate the association of (P)RR with mesangial fibrosis or expansion. Furthermore, we examined the correlation between serum soluble (P)RR [s(P)RR] and various laboratory data including serum IS, a uremic toxin that induces renal fibrosis through (P)RR, and pathological indices in chronic kidney disease and particularly in IgA nephropathy patients. In vitro study using SV40 MES13 cells revealed that (P)RR expression significantly increased in the presence of IS. IS stimulated the fibrotic factors' expression, which was significantly suppressed by (P)RR knockdown. Moreover, it significantly increased the expression of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 via the ERK1/2 pathway. In addition, the s(P)RR level significantly correlated with serum IS and mesangial injury markers in our patients. Our results suggest that (P)RR is associated with mesangial fibrosis and matrix expansion through the IS-(P)RR-ERK1/2 pathway. Clinically, s(P)RR may be a biomarker of mesangial fibrosis and matrix expansion.
（前）肾素受体 [(P)RR] 在肾脏中表达，并参与肾脏损伤。虽然（P）RR 被吲哚硫酸酯（IS）激活，并且可能与肾脏损伤有关，但细节尚不清楚。我们使用小鼠系膜细胞系 SV40 MES13 来研究（P）RR 与系膜纤维化或扩张的关系。此外，我们检查了血清可溶性（P）RR [s（P）RR] 与各种实验室数据之间的相关性，包括血清 IS，IS 通过（P）RR 诱导肾脏纤维化的尿毒症毒素，以及慢性肾脏病患者，尤其是 IgA 肾病患者的病理指标。SV40 MES13 细胞的体外研究表明，（P）RR 的表达在 IS 存在的情况下显著增加。IS 刺激纤维化因子的表达，而（P）RR 敲低显著抑制其表达。此外，它通过 ERK1/2 途径显著增加基质金属蛋白酶 9 和组织金属蛋白酶抑制剂 1 的表达。此外，s（P）RR 水平与我们患者的血清 IS 和系膜损伤标志物显著相关。我们的结果表明，（P）RR 通过 IS-（P）RR-ERK1/2 途径与系膜纤维化和基质扩张有关。临床上，s（P）RR 可能是系膜纤维化和基质扩张的生物标志物。
