(Pro)Renin Receptor Decoy Peptide PRO20 Protects against Oxidative Renal Damage Induced by Advanced Oxidation Protein Products

Abstract

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 (n = 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 H2O2 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 H2O2 mechanisms.

Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial*

“…4 , all panels , http://links.lww.com/CCM/H445 ). Elevated levels of renin may also bind and stimulate the (pro)renin receptor that is directly linked to oxidative stress and fibrosis ( 31 ). Thus, it is possible that vitamin C may counteract this maladaptive response by reducing oxidative stress during the hyperreninergic response in septic shock.…”

Therapeutic potential of Ganoderma lucidum polysaccharide peptide in Doxorubicin-induced nephropathy: modulation of renin-angiotensin system and proteinuria

“…The PRR is a crucial part of the RAS, increasing renin activity by binding and activating the intrarenal RAS (Nguyen et al, 2002). PRR has been shown to exacerbate renal failure and proteinuria levels in various animal models, including the 5/6 renal nephrectomy rat model , the protein overload rat model (Fang et al, 2018), the AOPPs-induced model (Fang et al, 2023), and the DOX-induced model (Luo et al, 2020), by activating the intrarenal RAS and causing inflammation, oxidative stress, and renal fibrosis. Additionally, higher levels of the 28 kDa product, sPRR, produced by protease-mediated cleavage of PRR, which indicates active RAS, have been seen in CKD patients (Cousin et al, 2009;Yoshikawa et al, 2011;Fang et al, 2017;Gatineau et al, 2019;Xie et al, 2020).…”

“…The identical steps as previously described for performing a Western Blot were followed (Fang et al, 2023). Protein determination was performed using a bicinchoninic acid protein assay kit (P0010, Beyotime, Shanghai, China) (Yi et al, 2021).…”

“…The kidney tissue sections were stained using the schiff periodic acid shiff (PAS) staining agent to assist in histological evaluation using a light microscope (Nexcope NIB610,Ningbo Yongxin Optics Co.,Ltd.,Ningbo,China). We employed a previously established scoring system for evaluating the extent of damage in the renal tubules and glomeruli (Dhande et al, 2017;Fang et al, 2023). The assessment of renal tubular injury was conducted blindly, taking into account factors such as tubular atrophy, dilation, protein casts, and infiltration of inflammatory cells.…”

“…The (pro) renin receptor (PRR) in the RAS is recognized as a significant regulator of blood pressure, as well as a mediator of various physiological processes (Ichihara and Yatabe, 2019). PRR has been shown to play a pivotal role in mediating the pathological effects induced by Ang Ⅱ (Wang et al, 2014), protein load (Fang et al, 2018), advanced oxidation protein products (AOPPs) (Fang et al, 2023), and DOX-induced renal disease (Luo et al, 2020). These findings highlight both the significance of PRR as a possible therapeutic target for treating renal disorders and the opportunities for innovative therapies.…”