Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling

Abstract

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 μg/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 μM) 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 H2O2 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 H2O2 contributed to the aggravation of oxidative stress. Targeting S1P-derived sPRR is a promising intervention strategy for chronic kidney disease.

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

“…Based on our previous study, AOPPs-RSA was shown to cause injury to kidney tubular epithelial cells by activating the PRR/Nox4/H 2 O 2 pathway [ 16 ]. As expected, we found that AOPPs-RSA administration also significantly increased urinary and renal cortical H 2 O 2 excretion, and PRO20 treatment antagonized these responses ( p < 0.05) ( Figure 4 D,E).…”

“…The present study aimed to investigate the potential of Nox4 as a therapeutic target for AOPPs-RSA-induced kidney disease by examining its role in the pathogenesis of AOPPs-RSA. In vitro, we observed that AOPPs-HSA upregulated Nox4 expression in human HK-2 cells [ 16 ]. Furthermore, the present study demonstrated that AOPPs-RSA can upregulate NOX4 expression and generate H 2 O 2 in AOPPs-RSA rats, suggesting that AOPPs-RSA/NOX4 are capable of forming a positive feedback loop via H 2 O 2 .…”

“…Reactive oxygen species (ROS) from NADPH oxidase 4 (Nox4) contribute to oxidative stress and fibrosis in the kidney [ 14 , 15 ]. Our recent study showed that soluble PRR (sPRR) mediates AOPP-induced renal epithelial cell injury via the augmented Nox4-derived hydrogen peroxide (H 2 O 2 ) pathway [ 16 ]. As a consequence, the PRR might be able to regulate Nox4/H 2 O 2 signaling during AOPP-induced nephropathy in rats.…”

“…In recent years, ample studies have validated the effectiveness of PRO20 in attenuating the hyperactivation of intrarenal RAS in hypertensive rats who are deficient in drinking water, high in potassium, high in fructose and salts, overloaded with albumin, and injected with Adriamycin, prorenin, and Ang II [ 9 , 18 , 19 , 20 , 21 , 22 ]. We have previously shown that the PRR controls Nox4-derived H 2 O 2 synthesis in cultured human proximal tubular epithelial HK2 cells by regulating the intrarenal RAS, and these results implicate the PRR in regulating AOPP-induced oxidative stress and potential inflammation effects [ 16 ]. As of yet, it is unknown whether the PRR regulates in vivo.…”

The role of (pro)renin receptor and its soluble form in cardiovascular diseases

“…However, recent studies on sPRR, especially the effect of sPRR activating AT1R, implied that sPRR might also participate in heart disease pathogenesis, which requires further study. Some researchers have suggested that sPRR led to tissue fibrosis via the PI3K-AKT pathway and could also cause oxidative stress via NOX4 in renal proximal tubular cell lines ( 91 , 92 ). It is still not clear whether sPRR has the same effect on the myocardium.…”