Systemic factors related to soluble (pro)renin receptor in plasma of patients with proliferative diabetic retinopathy

<div><p>(Pro)renin receptor [(P)RR], a new component of the tissue renin-angiotensin system (RAS), plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy (PDR). In this study, we investigated systemic factors related to plasma levels of soluble form of (P)RR [s(P)RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s(P)RR, prorenin, tumor necrosis factor (TNF)-α, complement factor D (CFD), and leucine-rich α-2-glycoprotein 1 (LRG1) significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s(P)RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s(P)RR, but not prorenin, levels. Among the inflammatory molecules correlated with s(P)RR in the plasma, TNF-α, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of (P)RR but not prorenin, while stimulation with high glucose enhanced both (P)RR and prorenin expression. These findings suggested close relationships between plasma s(P)RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR.</p></div

Plasma concentrations of inflammatory and angiogenic molecules.

<p>Plasma concentrations of inflammatory and angiogenic molecules.</p

Upregulation of s(P)RR, prorenin and activated prorenin protein levels in the plasma of PDR patients.

<p>Protein levels of s(P)RR (A), prorenin (B), and activated prorenin (C) in the plasma of the non-DM and PDR subjects. Black symbols indicate individual samples. n = 20 in each group, **<i>p</i> < 0.01, Student’s t test. (D) Correlation between s(P)RR and prorenin was not detected in the plasma of patients with PDR (n = 20, Spearman rank correlation).</p

Basal characteristics of participating patients.

<p>Basal characteristics of participating patients.</p

Association of plasma s(P)RR with chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR.

<p>A schema showing diabetes-induced factors such as chronic inflammation, renal dysfunction, and hyperglycemia as the potential regulators of plasma s(P)RR and prorenin levels, thus initiating the RAS activation to enhance retinal neovascularization (NV), the hallmark of PDR. Retinal NV, in turn, functions as a cellular source of these RAS initiators under hyperglycemia, generating the vicious cycle of RAS and PDR. Arrows indicate cause-effect relations, and lines represent correlations.</p

Correlations between plasma s(P)RR and renal dysfunction parameters.

<p>Correlations between s(P)RR and renal dysfunction parameters eGFR (A) and sCr (B) in the plasma of patients with PDR. (n = 20, Spearman rank correlation). Correlations between prorenin and renal dysfunction parameters eGFR (C) and sCr (D) were not detected in the plasma of patients with PDR (n = 20, Spearman rank correlation).</p

Correlations between prorenin and inflammatory mediators elevated in the plasma of PDR patients.

<p>Correlations between prorenin and inflammatory mediators TNF-α (A), CFD (B), LRG1 (C) and VAP-1 (D) in the plasma of patients with PDR (n = 20, Spearman rank correlation).</p