(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy

Abstract

The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis.

Keywords: (Pro)renin receptor; Diabetic retinopathy; Receptor-associated prorenin system.

Figure 1

Molecular mechanisms in retinal (a) receptor‐associated prorenin system (RAPS) and (b) vitreous renin–angiotensin system (RAS) leading to vascular endothelial growth factor (VEGF)‐driven pathogenesis of diabetic retinopathy. Retinal RAPS is required for membrane‐type (pro)renin receptor ([P]RR), whereas vitreous RAS is caused by a soluble form of (P)RR (s[P]RR). Even when membrane‐bound (P)RR is truncated into its soluble form, s(P)RR, it continues to affect the pathogenesis driven by angiotensin II signaling. ERK, extracellular signal‐regulated kinase; NF‐κB, Nuclear factor‐κB. Reproduced from Kanda et al.30 with permission.

Figure 2

Association of plasma a soluble form of (pro)renin receptor (s[P]RR) with chronic inflammation, renal dysfunction and hyperglycemia in patients with proliferative diabetic retinopathy (PDR). 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 renin–angiotensin system 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 the renin–angiotensin system and PDR. Arrows indicate cause–effect relationships, and lines represent correlations. CFD, complement factor D; LRG1, rich α‐2‐glycoprotein 1; PDH, pyruvate dehydrogenase; PDHB, pyruvate dehydrogenase E1 β subunit; TNF‐α, tumor necrosis factor‐α. Reproduced from Hase et al.43 with permission.

Figure 3

ATP6AP2/(pro)renin receptor involvement in pyruvate dehydrogenase (PDH)‐mediated aerobic glucose metabolism and oxidative stress. ATP6AP2/(pro)renin receptor blockade causes a metabolic shift from aerobic cellular respiration to anaerobic glycolysis (green arrows), leading consequently to a decrease in mitochondrial reactive oxygen species (ROS). Reproduced from Kanda et al.31 with permission. PDHB, pyruvate dehydrogenase E1 β subunit; TCA, tricarboxylic acid.

Figure 4

Impaired retinal development in photoreceptor‐specific Atp6ap2‐deficient mouse. (a) Normal and (b) photoreceptor‐specific Atp6ap2 deficient mouse retina. Atp6ap2/(pro)renin receptor binds to partitioning defective 3 homolog (Par3) as a cell polarity determinant required for retinal laminar organization during physiological development. Modified from Kanda et al.32 with permission. aPKCλ, atypical protein kinase Cλ.

Figure 5

Binding partners and biological functions of (pro)renin receptor ([P]RR)/ATP6AP2. (P)RR/ATP6AP2 interacts with various molecules to exert distinctly different functions. PAR3, partitioning defective 3 homolog; PDHB, pyruvate dehydrogenase E1 β subunit; RAPS, receptor‐associated prorenin system; v‐ATPase, vacuolar‐type H⁺‐adenosine triphosphatase.

Figure 6

Structure of proline‐modified short hairpin ribonucleic acid (PshRNA). Structure of canonical double‐strand small interfering RNA (siRNA) and novel single‐strand RNA interference (PshRNA) agents. Blue circles indicate the sense strand of a target gene, red circles are the antisense strand and yellow circles are the linker region. P indicates a proline derivative. RNAi, ribonucleic acid interference.