Involvement of the Receptor-Associated Prorenin System in the Pathogenesis of Human Conjunctival Lymphoma

Ishida

2018

J of Diabetes Invest

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.

Section: Development Of a Novel Single‐strand Rna Interference Therapmentioning

confidence: 70%

Section: (Pro)renin Receptor In Uveitismentioning

confidence: 99%

Section: Development Of a Novel Single-strand Rna Interference Therapmentioning

confidence: 99%

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

Ishida

2018

J of Diabetes Invest

“…We previously revealed the significant contribution of the AT1R and (P)RR signaling pathways to upregulated expression of pathogenic molecules such as ICAM-1, IL-6, CCL2/MCP-1, and VEGF-A, and thus the association of RAS and RAPS with ocular inflammation and neovascularization in animal disease models and human clinical samples 9, 10, 11, 12, 13, 14, 15, 20, 21, 28, 29. In our current study, we newly demonstrate elevated vitreous levels of prorenin and s(P)RR in patients with uveitis, as well as the significant correlation between these RAPS components and CCL2/MCP-1 levels.…”

Section: Discussionmentioning

confidence: 99%

A Novel Single-Strand RNAi Therapeutic Agent Targeting the (Pro)renin Receptor Suppresses Ocular Inflammation

Molecular Therapy - Nucleic Acids

Ishizuka

Shibata

et al. 2017

The receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to the (pro)renin receptor [(P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble (P)RR levels in the vitreous fluid of patients with uveitis compared to non-inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline-modified short hairpin RNA directed against human and mouse (P)RR [(P)RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of (P)RR-PshRNA in mice caused significant amelioration of acute (uveitic) and chronic (diabetic) models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of (P)RR-PshRNA as a therapeutic agent to reduce ocular inflammation.

“…These data indicate that the vitreous renin activity stems from s(P)RR-mediated non-proteolytic activation of prorenin, suggesting the significant role of (P)RR in the pathogenesis of PDR. Indeed, (P)RR and RAS components were expressed in diabetic fibrovascular tissues, human retinal cell lines, and normal ocular tissues [ 26 , 28 – 30 ], and the vitreous levels of prorenin and angiotensin II (Ang II) were shown to be elevated in PDR eyes [ 31 – 34 ]. Furthermore, a close link between the vitreous renin activity and VEGF protein levels validates our concept of vitreous RAS that contributes to the angiogenic activity of DR. Consequently, in concert with vitreous RAS due to s(P)RR (Fig.…”

Section: Vitreous Renin-angiotensin System and Retinal Receptor-assocmentioning

confidence: 99%

Receptor-associated prorenin system contributes to development of inflammation and angiogenesis in proliferative diabetic retinopathy

Ishida

2016

Inflamm Regener

The renin-angiotensin system (RAS) plays a potential role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor of several diseases including diabetes. So far, using animal disease models, we have shown molecular mechanisms, in which tissue RAS stimulates retinal angiogenesis, and the critical roles of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction, referred to as the receptor-associated prorenin system (RAPS). Moreover, we recently reported that the protein levels of prorenin and soluble (P)RR increased in the vitreous fluids obtained from patients with proliferative diabetic retinopathy (PDR), suggesting the association of (P)RR with vascular endothelial growth factor (VEGF)-driven angiogenic activity in human PDR, and also showed a close relationship between the vitreous renin activity and VEGF-induced pathogenesis of diabetic retinopathy. Our data using animal disease models and human clinical samples suggest that both vitreous RAS and retinal RAPS play critical roles in the molecular pathogenesis of diabetic retinopathy.