Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, 261053 Shandong, China.
Oxid Med Cell Longev. 2021 Nov 26;2021:5710440. doi: 10.1155/2021/5710440. eCollection 2021.
Full-length (pro)renin receptor (fPRR), a research hotspot of the renin-angiotensin system (RAS), plays a serious role in kidney injury. However, the relationship between fPRR and advanced oxidation protein product (AOPP) remains largely unexplored. This study was aimed at exploring the effect of fPRR, especially its 28 kDa soluble form called soluble PRR (sPRR), in AOPP-induced oxidative stress in HK-2 cells, a renal proximal tubular epithelial cell line. Incubation of HK-2 cells with 100 g/ml AOPP resulted in significant upregulation of fPRR expression and caused an approximately fourfold increase in medium sPRR secretion. However, unmodified albumin did not demonstrate the same effects under the same concentration. Treatment of HK-2 cells with the site-1 protease (S1P) inhibitor PF429242 (40 M) or S1P siRNA significantly inhibited AOPP-induced sPRR generation. fPRR decoy inhibitor PRO20 and PF429242 treatment for 24 h remarkably attenuated the AOPP-induced upregulation of RAS components. Furthermore, PF429242 significantly reduced the AOPP-stimulated expression of NADPH oxidase 4 (Nox4) and HO expression. The use of a small recombinant protein, named sPRR-His, reversed these alterations. In conclusion, these results provided the first demonstration of AOPP-promoted activation of sPRR. Increased renal proximal tubule Nox4-derived HO contributed to the aggravation of oxidative stress. Targeting S1P-derived sPRR is a promising intervention strategy for chronic kidney disease.
全长（前）肾素受体（fPRR）是肾素-血管紧张素系统（RAS）的研究热点，在肾损伤中起重要作用。然而，fPRR 与晚期氧化蛋白产物（AOPP）之间的关系在很大程度上尚未得到探索。本研究旨在探讨 fPRR，特别是其 28 kDa 的可溶性形式即可溶性 PRR（sPRR），在 AOPP 诱导的 HK-2 细胞（一种肾近端肾小管上皮细胞系）氧化应激中的作用。用 100 μg/ml AOPP 孵育 HK-2 细胞可显著上调 fPRR 的表达，并使培养基中 sPRR 的分泌增加约 4 倍。然而，相同浓度下未修饰的白蛋白没有表现出相同的作用。用位点 1 蛋白酶（S1P）抑制剂 PF429242（40 μM）或 S1P siRNA 处理 HK-2 细胞可显著抑制 AOPP 诱导的 sPRR 生成。fPRR 诱饵抑制剂 PRO20 和 PF429242 处理 24 h 可显著减弱 AOPP 诱导的 RAS 成分的上调。此外，PF429242 显著降低了 AOPP 刺激的 NADPH 氧化酶 4（Nox4）和 HO 的表达。使用一种名为 sPRR-His 的小重组蛋白逆转了这些改变。总之，这些结果首次证明了 AOPP 促进 sPRR 的激活。增加的肾近端小管 Nox4 衍生的 HO 导致氧化应激的加重。靶向 S1P 衍生的 sPRR 是慢性肾脏病的一种有前途的干预策略。
