School of Pharmacy, Weifang Medical University, Weifang 261053, China.
Molecules. 2023 Mar 28;28(7):3017. doi: 10.3390/molecules28073017.
Chronic kidney disease (CKD) is associated with advanced oxidation protein products (AOPPs). A recent study has shown that AOPP-induced renal tubular injury is mediated by the (pro)renin receptor (PRR). However, it is unclear whether the PRR decoy inhibitor PRO20 can protect against renal damage related to AOPPs in vivo. In this study, we examined the role of the PRR in rats with AOPP-induced renal oxidative damage. Male SD rats were subjected to unilateral nephrectomy, and after a four-day recuperation period, they were randomly divided into four groups ( = 6/group) for four weeks: control (CTR), unmodified rat serum albumin (RSA, 50 mg/kg/day via tail-vein injection), AOPPs-RSA (50 mg/kg/day via tail-vein injection), and AOPPs-RSA + PRO20 (50 mg/kg/day via tail-vein injection + 500 μg/kg/day via subcutaneous injection) groups. PRO20 was administered 3 days before AOPPs-RSA injection. Renal histopathology evaluation was performed by periodic acid-Schiff (PAS) staining, and biochemical parameters related to renal injury and oxidative stress biomarkers were evaluated. The expression of related indicators was quantified by RT-qPCR and immunoblotting analysis. In the results, rats in the AOPPs-RSA group exhibited higher levels of albuminuria, inflammatory cell infiltration, and tubular dilation, along with upregulation of oxidative stress, profibrotic and proinflammatory factors, and elevation of AOPP levels. Meanwhile, in the PRO20 group, these were significantly reduced. Moreover, the levels of almost all components of the renin-angiotensin system (RAS) and Nox4-dependent HO production in urine and the kidneys were elevated by AOPPs-RSA, while they were suppressed by PRO20. Furthermore, AOPPs-RSA rats showed elevated kidney expression of the PRR and soluble PRR (sPRR) and increased renal excretion of sPRR. In summary, these findings suggest that PRR inhibition may serve as a protective mechanism against AOPP-induced nephropathy by inhibiting the intrarenal RAS and Nox4-derived HO mechanisms.
慢性肾脏病（CKD）与晚期氧化蛋白产物（AOPPs）有关。最近的一项研究表明，AOPP 诱导的肾小管损伤是由（前）肾素受体（PRR）介导的。然而，尚不清楚 PRR 诱饵抑制剂 PRO20 是否可以在体内防止与 AOPPs 相关的肾损伤。在这项研究中，我们研究了 PRR 在 AOPP 诱导的肾氧化损伤大鼠中的作用。雄性 SD 大鼠接受单侧肾切除术，在四天恢复期后，随机分为四组（每组 6 只），持续四周：对照组（CTR）、未修饰的牛血清白蛋白（RSA，50mg/kg/天经尾静脉注射）、AOPPs-RSA（50mg/kg/天经尾静脉注射）和 AOPPs-RSA+PRO20（50mg/kg/天经尾静脉注射+500μg/kg/天经皮下注射）组。在给予 AOPPs-RSA 前三天给予 PRO20。通过过碘酸-Schiff（PAS）染色进行肾组织病理学评估，并评估与肾损伤和氧化应激生物标志物相关的生化参数。通过 RT-qPCR 和免疫印迹分析定量相关指标的表达。结果显示，AOPPs-RSA 组大鼠出现更高水平的蛋白尿、炎症细胞浸润和肾小管扩张，同时氧化应激、促纤维化和促炎因子上调，AOPP 水平升高。同时，在 PRO20 组中，这些明显减少。此外，AOPPs-RSA 升高了尿液和肾脏中肾素-血管紧张素系统（RAS）和 Nox4 依赖性 HO 产生的几乎所有成分的水平，而 PRO20 抑制了这些成分的水平。此外，AOPPs-RSA 大鼠的肾脏 PRR 和可溶性 PRR（sPRR）表达升高，肾脏 sPRR 排泄增加。总之，这些发现表明，PRR 抑制可能通过抑制肾内 RAS 和 Nox4 衍生的 HO 机制，成为一种针对 AOPP 诱导的肾病的保护机制。
