[Frontiers in Bioscience S4, 1449-1460, June 1, 2012]
Receptor-associated prorenin system in the pathogenesis of retinal diseases
Shingo Satofuka1,2, Atsuhiro Kanda3, Susumu Ishida2,3
1
TABLE OF CONTENTS
1. ABSTRACT
Receptor-associated prorenin system (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to (pro)renin receptor ((P)RR) dually activates tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling through the receptor. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R) in intraocular inflammation and neovascularization, central pathologies of age-related macular degeneration and diabetic retinopathy, the association of RAPS with these vision-threatening disorders has not been defined. (P)RR blockade to murine disease models led to significant suppression of laser-induced choroidal neovascularization and diabetes-induced retinal inflammation together with the upregulation of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and vascular endothelial growth factor (VEGF). Either the genetic ablation or the pharmacological blockade of AT1-R exhibited significant reduction of choroidal and retinal abnormalities, both of which were further suppressed by (P)RR blockade. (P)RR blockade inhibited ERK activation and the production of VEGF and MCP-1, but not ICAM-1, in AT1-R-deficient mice with retinal and choroidal disorders. These recent findings indicate significant contribution of RAPS to the pathogenesis of age-related macular degeneration and diabetic retinopathy.
2. INTRODUCTION
(Pro)renin receptor ((P)RR), also called ATP6AP2, was identified as a single transmembrane protein consisting of 350 amino acids. The fragment (P)RR has been shown to be associated with vacuolar-type H+-ATPase (V-ATPase) and required for Wnt/ß-catenin signaling pathway (1). In addition to its role for vesicular acidification, (P)RR interacts with its ligand prorenin to exert renin activity through the conformational change of the prorenin molecule instead of the conventional proteolysis of the prorenin prosegment basically achieved by processing enzymes (Figure 1A). Since the membrane-bound (P)RR is reported to exist in the major organs but not in the circulation (2), the nonproteolytic activation of prorenin is hypothesized to play a critical role in the activation of tissue, but not circulatory, renin-angiotensin system (RAS). In addition, prorenin binding to its receptor is shown to cause RAS-independent signal transduction via phosphorylation of ERK (extracellular signal-regulated kinase) 1/2 in cells bearing (P)RR (2-5). Thus, we proposed the nomenclature "receptor-associated prorenin system (RAPS)" for the dual activation of tissue RAS and RAS-independent signaling pathway. In streptozotocin (STZ)-induced diabetes, blockade of prorenin binding to its receptor led to complete suppression of proteinuria, glomerulosclerosis and renal production of angiotensin I and II without affecting circulatory RAS, indicating a critical contribution of RAPS to the pathogenesis of diabetic nephropathy (4, 6-8).
Choroidal neovascularization (CNV) and diabetes-induced retinal inflammation is a hallmark of vision-threatening disorders, including age-related macular degeneration (AMD) and diabetic macular edema, both of which are the major causes of central vision loss. We reported that tissue RAS was upregulated and angiotensin II type 1 receptor (AT1-R) signaling plays crucial roles in choroidal and retinal neovascularization (9, 10) by inducing several angiogenic and inflammatory factors. Although we further showed that tissue RAS for promoting retinal inflammation (11) and neovascularization (12) is triggered by (P)RR-induced nonproteolytic activation of prorenin, it was not determined whether (P)RR-mediated intracellular signaling, the other pathway of RAPS, is pathogenic in the eye.
We therefore hypothesized that prorenin binding to its receptor promotes CNV and diabetes-induced retinal inflammation by dually activating tissue RAS and RAS-independent ERK pathway as an intracellular signaling via the receptor. Recently, we reported the first evidence of significant relationship between RAPS and these choroidal and retinal disorders together with underlying molecular and cellular mechanisms (13, 14).
3. BLOCKADE OF PRORENIN BINDING TO (P)RR
To cover the handle region (positions 11-15) of the prorenin molecule, which is the binding site of (P)RR (15), we designed decoy peptides, NH2-RILLKKMPSV-COOH and NH2-IPLKKMPS-COOH as rat and mouse (P)RR blockers (PRRBs) (Figure 1B), respectively, and purified them by high-pressure liquid chromatography on a C-18 reverse-phase column, as described previously (4, 6-8, 11, 16). The specific inhibitory action of PRRB against prorenin binding with (P)RR and subsequent ERK activation was confirmed in recent in vitro data (14, 17, 18). The specific inhibitory action of PRRB against tissue RAS or RAPS in vivo was also confirmed in other reports (4, 6-8, 11-14, 16). As a negative control, rat PRRB was inactivated by heat denaturation at 100�C for 10 min and used as control peptide (CP). We also generated a scramble peptide (SP) NH2-KPMLISKP-COOH for mouse PRRB as another negative control.
4. PATHOLOGIC ROLE OF (P)RR IN THE EYE
4.1. AMD
4.1.1. CNV and tissue RAS
AMD, the most common cause of blindness in developed countries, is complicated by CNV leading to severe vision loss due to hemorrhage and exudation from the immature new vessels (19, 20). Epidemiologic risk factors for AMD were reported to include hypertension, dyslipidemia, and atherosclerosis, all of which are related to the metabolic syndrome (21, 22). AT1-R signaling was shown to play a significant role in various pathologic processes such as angiogenesis and inflammation, both of which complicate the metabolic syndrome (23-26). CNV proved to be an inflammatory disorder depending on intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and vascular endothelial growth factor (VEGF) (27). We showed that AT1-R-mediated upregulation of these inflammatory and angiogenic molecules is required for the development of CNV (9).
4.1.2. Pathologic roles of (P)RR in CNV
We revealed several important findings concerning the role of (P)RR in CNV generation (13). First, CNV development was associated with upregulation of prorenin mRNA expression, but not (P)RR, in the retinal pigment epithelium (RPE)-choroid complex and PRRB treatment showed a significant decrease in the CNV volume, indicating that prorenin binding with its receptor contributes to CNV (Figure 2). Second, the cellular and molecular mechanisms in the PRRB-induced suppression of CNV included the inhibitory effects on macrophage infiltration into CNV, angiotensin II generation and the upregulated expression of inflammatory and angiogenic molecules such as ICAM-1, MCP-1, VEGF, VEGF receptor (VEGFR)-1 and VEGFR-2, all of which were downstream molecules of angiotensin II (Figure 3) (9). Although the detailed molecular and cellular mechanisms underlying CNV are not fully clarified, ICAM-1 expression (28, 29) and macrophage infiltration (9, 27) were observed in CNV tissues from human eyes with AMD and the laser-induced murine model, suggesting the close association of inflammation with the progression of CNV. Pharmacologic depletion of macrophages (30, 31) or genetic ablation of CCR2 (32), a receptor for MCP-1, was shown to result in the reduction of CNV, suggesting that macrophages, recruited by MCP-1 released from RPE or vascular endothelial cells, facilitate the development of CNV by producing VEGF. In concert with our previous data (9), PRRB-induced suppression of CNV indicates that tissue RAS is activated during CNV by (P)RR-mediated nonproteolytic activation of prorenin, leading to AT1-R signaling-mediated upregulation of CNV-related inflammatory molecules.
To elucidate the involvement of RAPS comprising both (P)RR-mediated signal transduction and tissue RAS activation, we studied the role of RAS-independent (P)RR signaling in CNV generation (Figure 4). (P)RR signaling was shown to contribute to the pathogenesis of diabetic nephropathy using AT1-R-deficient mice (6). AT1-R-deficient mice with streptozotocin (STZ)-induced diabetes exhibited reduced proteinuria and glomerulosclerosis in the early phase as compared to STZ-treated wild-type mice, indicating a significant role of tissue RAS in diabetic nephropathy. Surprisingly, these renal events in AT1-R-deficient diabetes later progressed to the equivalent levels seen in diabetic wild-type mice. The glomerulosclerosis observed in AT1-R-deficient diabetic mice was associated with ERK activation, which was completely blocked together with the phenotype by sustained application of PRRB, suggesting that the redundant pathways of RAPS were involved in the pathogenesis of diabetic nephropathy. We administered PRRB to CNV mice receiving the AT1-R blocker losartan or genetically deficient in AT1-R or angiotensinogen (AGT), and these three different methods for deactivating RAS confirmed the significant role of intracellular signaling via (P)RR in the development of CNV (Figure 4A, B). The data were compatible with the result of parallel experiments showing that macrophage infiltration into CNV was also suppressed by PRRB in AGT-deficient mice (Figure 4C, D). PRRB application to AT1-R-deficient mice with CNV led to significant suppression of ERK activation (Figure 5A, B). Out of the CNV-related molecules, the expression of which was inhibited by PRRB (Figure 3 E-I), MCP-1 (Figure 5C) and VEGF (Figure 5D), but not ICAM-1, VEGFR-1 or VEGFR-2 (data not shown), were also regulated by (P)RR signaling per se. These results revealed that molecular and cellular mechanisms mediated by RAS-independent intracellular signaling via (P)RR is involved in CNV generation (Figures 4, 5). This is the first report to show that RAPS is associated with inflammation and angiogenesis in the eye (13), in consistence with previous reports showing that RAPS contributes to glomerulosclerosis in the kidney and fibrosis in the heart (4, 6, 7, 16). Moreover, we reported that nonproteolytic activation of prorenin selectively accelerates pathologic, but not physiologic, retinal neovascularization via the inflammatory processes in ischemia-induced retinal neovascularization (12). Recently, PRRB was also shown to exert anti-angiogenic and anti-inflammatory effects in ischemia-induced retinal neovascularization (33), which confirmed our previous data; however, PRRB-induced injury to retinal neurons was simultaneously observed in contrast with its protective effect on the retinal vasculature.
4.2. Diabetic retinopathy
4.2.1. Diabetic retinopathy and tissue RAS
AT1-R protein was expressed in the fibrovascular tissues surgically excised from human eyes with proliferative diabetic retinopathy and tissue RAS is activated in the retina of mice with STZ-induced diabetes (34). Diabetic retinopathy proved to be an inflammatory disorder depending on VEGF and ICAM-1 (35-39). We showed that diabetes-induced upregulation of these inflammatory and angiogenic molecules is mediated by AT1-R signaling and required for diabetes-induced retinal leukocyte adhesion (34), indicating the association of tissue RAS with diabetic retinopathy. This is supported by several studies showing that RAS contributes to various pathologic vascular conditions including inflammation and neovascularization via AT1-R signaling (40-43).
4.2.2. Pathologic roles of (P)RR in diabetes-induced retinal inflammation
Recent studies revealed that (P)RR was localized to vascular endothelial cells, pericytes, glia and ganglion cells in the rodent retina (14, 33) and human RPE cells (44). Photoreceptor morphology was abnormal in (P)RR conditional knockout mice (A.K., S.I. et al.; unpublished data), suggesting that (P)RR has a physiologic role during photoreceptor development. On the other hand, microvascular expression of (P)RR in the retina led us to hypothesize its involvement with the pathogenesis of diabetic retinopathy. We recently reported that several important findings concerning the role of (P)RR in diabetes-induced retinal inflammation (14). Diabetes-induced leukocyte adhesion to the retinal vasculature was suppressed by PRRB treatment, indicating that prorenin binding with its receptor contributes to the pathogenesis in the diabetic retina. The molecular mechanisms in the suppression of retinal leukocyte adhesion proved to include the inhibitory effects of PRRB on retinal expression of VEGF and ICAM-1, both of which are known as key factors responsible for diabetes-induced retinal inflammation (Figure 6).
Molecular and cellular mechanisms underlying the pathogenesis of diabetic retinopathy are not fully understood; however, increasing evidence suggested that the involvement of inflammatory processes including cytokine upregulation and leukocyte infiltration, causing diabetic retinopathy being regarded as an inflammatory disease (36, 39, 45-47). Retinal vasculature in diabetes is accompanied by inflammatory cell adhesion (48), which triggers vascular hyperpermeability (36) and pathologic neovascularization (47). ICAM-1, constitutively expressed on vascular endothelial cells at a low level, is swiftly upregulated during inflammation, resulting in enhancement of leukocyte-endothelial interaction. Previous studies using donor eyes from diabetic subjects and experimentally induced diabetes demonstrated that retinal ICAM-1 expression was elevated together with leukocyte adhesion and infiltration (36, 45). VEGF, a potent angiogenic and pro-inflammatory factor, plays a central role in the pathogenesis of diabetic retinopathy. In patients with diabetic retinopathy, VEGF levels in the intraocular fluid were increased not only during the proliferative stage (37), but also during the nonproliferative stage characterized by diabetic macular edema (38). Interestingly, angiotensin II levels were elevated and correlated with VEGF levels in the vitreous fluid of patients with diabetic macular edema (49). Angiotensin II was shown to induce ICAM-1 (50) and VEGF (51) through AT1-R in previous in vivo and in vitro studies. Also in the murine model of STZ-induced diabetes, we showed that tissue RAS enhanced retinal expression of these inflammatory molecules and subsequent leukocyte adhesion to the retinal vasculature, all of which were suppressed by AT1-R blockade (34). In concert with the previous data, the currently observed PRRB-induced suppression of diabetes-induced retinal inflammation (Figure 6) indicates that tissue RAS is activated in the diabetic retina by (P)RR-mediated nonproteolytic activation of prorenin, leading to AT1-R signaling-mediated VEGF and ICAM-1 upregulation and retinal leukocyte adhesion.
We further revealed the involvement of RAPS in the pathogenesis of diabetic retinopathy. The use of two different methods of inactivating AT1-R confirmed that PRRB functioned to inhibit both RAS-dependent and -independent mechanisms underlying retinal leukocyte adhesion (Figure 7). We administered PRRB to diabetic mice treated with losartan (Figure 7A) or AT1-R-deficient diabetic mice (Figure 7B) and confirmed the significant role of intracellular signaling via (P)RR in the diabetes-induced retinal leukocyte adhesion. PRRB application to AT1-R-deficient diabetic mice led to significant suppression of ERK activation, a known key intracellular signaling through (P)RR (Figure 8A, B). Of diabetes-related inflammatory molecules, the expression of which was inhibited by PRRB (Figure 6F, G), VEGF, but not ICAM-1, was also regulated by (P)RR signaling per se (Figure 8C, D). The data are supported by and consistent with our recent report on CNV showing that (P)RR signaling selectively induces VEGF and MCP-1 out of several inflammatory and angiogenic molecules mediated by AT1-R (13). Furthermore, a recent study showed the involvement of (P)RR in the pathogenesis of diabetic nephropathy by the induction of inflammatory cytokines independently of renal RAS (52). Combined with these results, RAS-independent intracellular signaling pathway through (P)RR is associated with inflammation in diabetes-induced organ damage including retinopathy.
5. PERSPECTIVE
Although hypertension is a known risk factor for AMD and diabetic retinopathy (53, 54), there are indeed a large number of normotensive patients with AMD or diabetic retinopathy who have the potential risk of hypotension caused by the use of antihypertensive agents including AT1-R blockers and ACE inhibitors. In contrast, since (P)RR is present in the major organs but not in the circulation, PRRB does not affect circulatory RAS or systemic blood pressure (7, 8). Interestingly, PRRB treatment to mice with CNV or diabetes-induced retinal inflammation was shown to cause not only tissue RAS deactivation but also additional suppression of (P)RR signaling-mediated expression of MCP-1 and VEGF, the major factor responsible for the development of these angiogenic and inflammatory disorders. Consequently, inhibition of RAPS with PRRB may prove more useful as a novel therapeutic strategy for vision-threatening diseases including AMD and diabetic retinopathy than RAS suppression with conventional AT1-R blockers or angiotensin-converting enzyme inhibitors.
6. ACKNOWLEDGMENTS
This work was supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology (S.S.; grant-in-aid for scientific research, #18791296), the Tokyo Biochemical Research Foundation (A.K.) and the Northern Advancement Center for Science & Technology (A.K.).
7. REFERENCES
1. Cruciat, C. M., B. Ohkawara, S. P. Acebron, E. Karaulanov, C. Reinhard, D. Ingelfinger, M. Boutros & C. Niehrs: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327, 459-463(2010)
http://dx.doi.org/10.1126/science.1179802
PMid:20093472
2. Nguyen, G., F. Delarue, C. Burckle, L. Bouzhir, T. Giller & J. D. Sraer: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109, 1417-1427(2002)
PMid:12045255 PMCid:150992
3. Huang, Y., N. A. Noble, J. Zhang, C. Xu & W. A. Border: Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int 72, 45-52(2007)
http://dx.doi.org/10.1038/sj.ki.5002243
PMid:17396111
4. Ichihara, A., Y. Kaneshiro, T. Takemitsu, M. Sakoda, T. Nakagawa, A. Nishiyama, H. Kawachi, F. Shimizu & T. Inagami: Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage. J Am Soc Nephrol 17, 2495-2503(2006)
http://dx.doi.org/10.1681/ASN.2005121278
PMid:16885412
5. Kaneshiro, Y., A. Ichihara, M. Sakoda, T. Takemitsu, A. H. Nabi, M. N. Uddin, T. Nakagawa, A. Nishiyama, F. Suzuki, T. Inagami & H. Itoh: Slowly Progressive, Angiotensin II-Independent Glomerulosclerosis in Human (Pro)renin Receptor-Transgenic Rats. J Am Soc Nephrol 18, 1789-1795(2007)
http://dx.doi.org/10.1681/ASN.2006091062
PMid:17494887
6. Ichihara, A., F. Suzuki, T. Nakagawa, Y. Kaneshiro, T. Takemitsu, M. Sakoda, A. H. Nabi, A. Nishiyama, T. Sugaya, M. Hayashi & T. Inagami: Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol 17, 1950-1961(2006)
http://dx.doi.org/10.1681/ASN.2006010029
PMid:16738017
7. Ichihara, A., M. Hayashi, Y. Kaneshiro, F. Suzuki, T. Nakagawa, Y. Tada, Y. Koura, A. Nishiyama, H. Okada, M. N. Uddin, A. H. Nabi, Y. Ishida, T. Inagami & T. Saruta: Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J Clin Invest 114, 1128-1135(2004)
http://dx.doi.org/10.1172/JCI21398
PMid:15489960 PMCid:522242
8. Takahashi, H., A. Ichihara, Y. Kaneshiro, K. Inomata, M. Sakoda, T. Takemitsu, A. Nishiyama & H. Itoh: Regression of Nephropathy Developed in Diabetes by (Pro)renin Receptor Blockade. J Am Soc Nephrol 18, 2054-2061(2007)
http://dx.doi.org/10.1681/ASN.2006080820
PMid:17538189
9. Nagai, N., Y. Oike, K. Izumi-Nagai, T. Urano, Y. Kubota, K. Noda, Y. Ozawa, M. Inoue, K. Tsubota, T. Suda & S. Ishida: Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization. Arterioscler Thromb Vasc Biol 26, 2252-2259(2006)
http://dx.doi.org/10.1161/01.ATV.0000240050.15321.fe
PMid:16888236
10. Nagai, N., K. Noda, T. Urano, Y. Kubota, H. Shinoda, T. Koto, K. Shinoda, M. Inoue, T. Shiomi, E. Ikeda, K. Tsubota, T. Suda, Y. Oike & S. Ishida: Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci 46, 1078-1084(2005)
http://dx.doi.org/10.1167/iovs.04-1101
11. Satofuka, S., A. Ichihara, N. Nagai, K. Yamashiro, T. Koto, H. Shinoda, K. Noda, Y. Ozawa, M. Inoue, K. Tsubota, F. Suzuki, Y. Oike & S. Ishida: Suppression of ocular inflammation in endotoxin-induced uveitis by inhibiting nonproteolytic activation of prorenin. Invest Ophthalmol Vis Sci 47, 2686-2692(2006)
http://dx.doi.org/10.1167/iovs.05-1458
12. Satofuka, S., A. Ichihara, N. Nagai, T. Koto, H. Shinoda, K. Noda, Y. Ozawa, M. Inoue, K. Tsubota, H. Itoh, Y. Oike & S. Ishida: Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization. Invest Ophthalmol Vis Sci 48, 422-429(2007)
http://dx.doi.org/10.1167/iovs.06-0534
13. Satofuka, S., A. Ichihara, N. Nagai, K. Noda, Y. Ozawa, A. Fukamizu, K. Tsubota, H. Itoh, Y. Oike & S. Ishida: (Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system. Am J Pathol 173, 1911-1918(2008)
http://dx.doi.org/10.2353/ajpath.2008.080457
PMid:18974301 PMCid:2626401
14. Satofuka, S., A. Ichihara, N. Nagai, K. Noda, Y. Ozawa, A. Fukamizu, K. Tsubota, H. Itoh, Y. Oike & S. Ishida: (Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation. Diabetes 58, 1625-1633(2009)
http://dx.doi.org/10.2337/db08-0254
PMid:19389828 PMCid:2699867
15. Suzuki, F., M. Hayakawa, T. Nakagawa, U. M. Nasir, A. Ebihara, A. Iwasawa, Y. Ishida, Y. Nakamura & K. Murakami: Human prorenin has "gate and handle" regions for its non-proteolytic activation. J Biol Chem 278, 22217-22222(2003)
http://dx.doi.org/10.1074/jbc.M302579200
PMid:12684512
16. Ichihara, A., Y. Kaneshiro, T. Takemitsu, M. Sakoda, F. Suzuki, T. Nakagawa, A. Nishiyama, T. Inagami & M. Hayashi: Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 47, 894-900(2006)
http://dx.doi.org/10.1161/01.HYP.0000215838.48170.0b
PMid:16585419
17. Nurun, N. A., N. M. Uddin, T. Nakagawa, H. Iwata, A. Ichihara, T. Inagami & F. Suzuki: Role of "handle" region of prorenin prosegment in the non-proteolytic activation of prorenin by binding to membrane anchored (pro)renin receptor. Front Biosci 12, 4810-4817(2007)
http://dx.doi.org/10.2741/2429
PMid:17569611
18. He, M., L. Zhang, Y. Shao, X. Wang, Y. Huang, T. Yao & L. Lu: Inhibition of renin/prorenin receptor attenuated mesangial cell proliferation and reduced associated fibrotic factor release. Eur J Pharmacol 606, 155-161(2009)
http://dx.doi.org/10.1016/j.ejphar.2008.12.050
PMid:19174157
19. Ferris, F. L., 3rd, S. L. Fine & L. Hyman: Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 102, 1640-1642(1984)
PMid:6208888
20. Klein, R., Q. Wang, B. E. Klein, S. E. Moss & S. M. Meuer: The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 36, 182-191(1995)
PMid:7822146
21. Klein, R., B. E. Klein, S. C. Tomany & K. J. Cruickshanks: The association of cardiovascular disease with the long-term incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 110, 1273-1280(2003)
http://dx.doi.org/10.1016/S0161-6420(03)00599-2
22. van Leeuwen, R., M. K. Ikram, J. R. Vingerling, J. C. Witteman, A. Hofman & P. T. de Jong: Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 44, 3771-3777(2003)
http://dx.doi.org/10.1167/iovs.03-0121
23. Sola, S., M. Q. Mir, F. A. Cheema, N. Khan-Merchant, R. G. Menon, S. Parthasarathy & B. V. Khan: Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation 111, 343-348(2005)
http://dx.doi.org/10.1161/01.CIR.0000153272.48711.B9
PMid:15655130
24. Ferder, L., F. Inserra & M. Martinez-Maldonado: Inflammation and the metabolic syndrome: role of angiotensin II and oxidative stress. Curr Hypertens Rep 8, 191-198(2006)
http://dx.doi.org/10.1007/s11906-006-0050-7
PMid:17147916
25. Vaziri, N. D., Z. G. Xu, A. Shahkarami, K. T. Huang, B. Rodriguez-Iturbe & R. Natarajan: Role of AT-1 receptor in regulation of vascular MCP-1, IL-6, PAI-1, MAP kinase, and matrix expressions in obesity. Kidney Int 68, 2787-2793(2005)
http://dx.doi.org/10.1111/j.1523-1755.2005.00750.x
PMid:16316354
26. Brasier, A. R., A. Recinos, 3rd & M. S. Eledrisi: Vascular inflammation and the renin-angiotensin system. Arterioscler Thromb Vasc Biol 22, 1257-1266(2002)
http://dx.doi.org/10.1161/01.ATV.0000021412.56621.A2
PMid:12171785
27. Ishibashi, T., Y. Hata, H. Yoshikawa, K. Nakagawa, K. Sueishi & H. Inomata: Expression of vascular endothelial growth factor in experimental choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol 235, 159-167(1997)
http://dx.doi.org/10.1007/BF00941723
PMid:9085111
28. Sakurai, E., H. Taguchi, A. Anand, B. K. Ambati, E. S. Gragoudas, J. W. Miller, A. P. Adamis & J. Ambati: Targeted disruption of the CD18 or ICAM-1 gene inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci 44, 2743-2749(2003)
http://dx.doi.org/10.1167/iovs.02-1246
29. Yeh, D. C., D. V. Bula, J. W. Miller, E. S. Gragoudas & J. G. Arroyo: Expression of leukocyte adhesion molecules in human subfoveal choroidal neovascular membranes treated with and without photodynamic therapy. Invest Ophthalmol Vis Sci 45, 2368-2373(2004)
http://dx.doi.org/10.1167/iovs.03-0981
30. Sakurai, E., A. Anand, B. K. Ambati, N. van Rooijen & J. Ambati: Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44, 3578-3585(2003)
http://dx.doi.org/10.1167/iovs.03-0097
31. Espinosa-Heidmann, D. G., I. J. Suner, E. P. Hernandez, D. Monroy, K. G. Csaky & S. W. Cousins: Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44, 3586-3592(2003)
http://dx.doi.org/10.1167/iovs.03-0038
32. Tsutsumi, C., K. H. Sonoda, K. Egashira, H. Qiao, T. Hisatomi, S. Nakao, M. Ishibashi, I. F. Charo, T. Sakamoto, T. Murata & T. Ishibashi: The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J Leukoc Biol 74, 25-32(2003)
http://dx.doi.org/10.1189/jlb.0902436
PMid:12832439
33. Wilkinson-Berka, J. L., R. Heine, G. Tan, M. E. Cooper, K. M. Hatzopoulos, E. L. Fletcher, K. J. Binger, D. J. Campbell & A. G. Miller: RILLKKMPSV influences the vasculature, neurons and glia, and (pro)renin receptor expression in the retina. Hypertension 55, 1454-1460(2010)
http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.148221
PMid:20368504
34. Nagai, N., K. Izumi-Nagai, Y. Oike, T. Koto, S. Satofuka, Y. Ozawa, K. Yamashiro, M. Inoue, K. Tsubota, K. Umezawa & S. Ishida: Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. Invest Ophthalmol Vis Sci 48, 4342-4350(2007)
http://dx.doi.org/10.1167/iovs.06-1473
35. McLeod, D. S., D. J. Lefer, C. Merges & G. A. Lutty: Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol 147, 642-653(1995)
PMid:7545873 PMCid:1870979
36. Miyamoto, K., S. Khosrof, S. E. Bursell, R. Rohan, T. Murata, A. C. Clermont, L. P. Aiello, Y. Ogura & A. P. Adamis: Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A 96, 10836-10841(1999)
http://dx.doi.org/10.1073/pnas.96.19.10836
37. Aiello, L. P., R. L. Avery, P. G. Arrigg, B. A. Keyt, H. D. Jampel, S. T. Shah, L. R. Pasquale, H. Thieme, M. A. Iwamoto, J. E. Park & et al.: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331, 1480-1487(1994)
http://dx.doi.org/10.1056/NEJM199412013312203
PMid:7526212
38. Tanaka, Y., S. Katoh, S. Hori, M. Miura & H. Yamashita: Vascular endothelial growth factor in diabetic retinopathy. Lancet 349, 1520(1997)
http://dx.doi.org/10.1016/S0140-6736(05)62099-5
39. Ishida, S., T. Usui, K. Yamashiro, Y. Kaji, E. Ahmed, K. G. Carrasquillo, S. Amano, T. Hida, Y. Oguchi & A. P. Adamis: VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 44, 2155-2162(2003)
http://dx.doi.org/10.1167/iovs.02-0807
40. Candido, R., T. J. Allen, M. Lassila, Z. Cao, V. Thallas, M. E. Cooper & K. A. Jandeleit-Dahm: Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis. Circulation 109, 1536-1542(2004)
http://dx.doi.org/10.1161/01.CIR.0000124061.78478.94
PMid:15023892
41. Tamarat, R., J. S. Silvestre, M. Durie & B. I. Levy: Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest 82, 747-756(2002)
PMid:12065685
42. Egami, K., T. Murohara, T. Shimada, K. Sasaki, S. Shintani, T. Sugaya, M. Ishii, T. Akagi, H. Ikeda, T. Matsuishi & T. Imaizumi: Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest 112, 67-75(2003)
PMid:12840060 PMCid:162282
43. Moravski, C. J., D. J. Kelly, M. E. Cooper, R. E. Gilbert, J. F. Bertram, S. Shahinfar, S. L. Skinner & J. L. Wilkinson-Berka: Retinal neovascularization is prevented by blockade of the renin-angiotensin system. Hypertension 36, 1099-1104(2000)
PMid:11116132
44. Alcazar, O., S. W. Cousins, G. E. Striker & M. E. Marin-Castano: (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling. Exp Eye Res 89, 638-647(2009)
http://dx.doi.org/10.1016/j.exer.2009.06.014
PMid:19580809
45. Joussen, A. M., V. Poulaki, W. Qin, B. Kirchhof, N. Mitsiades, S. J. Wiegand, J. Rudge, G. D. Yancopoulos & A. P. Adamis: Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 160, 501-509(2002)
http://dx.doi.org/10.1016/S0002-9440(10)64869-9
46. Joussen, A. M., V. Poulaki, M. L. Le, K. Koizumi, C. Esser, H. Janicki, U. Schraermeyer, N. Kociok, S. Fauser, B. Kirchhof, T. S. Kern & A. P. Adamis: A central role for inflammation in the pathogenesis of diabetic retinopathy. Faseb J 18, 1450-1452(2004)
PMid:15231732
47. Ishida, S., T. Usui, K. Yamashiro, Y. Kaji, S. Amano, Y. Ogura, T. Hida, Y. Oguchi, J. Ambati, J. W. Miller, E. S. Gragoudas, Y. S. Ng, P. A. D'Amore, D. T. Shima & A. P. Adamis: VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 198, 483-489(2003)
http://dx.doi.org/10.1084/jem.20022027
PMid:12900522 PMCid:2194095
48. Miyamoto, K., N. Hiroshiba, A. Tsujikawa & Y. Ogura: In vivo demonstration of increased leukocyte entrapment in retinal microcirculation of diabetic rats. Invest Ophthalmol Vis Sci 39, 2190-2194(1998)
PMid:9761301
49. Funatsu, H., H. Yamashita, T. Ikeda, Y. Nakanishi, S. Kitano & S. Hori: Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders. Am J Ophthalmol 133, 537-543(2002)
http://dx.doi.org/10.1016/S0002-9394(02)01323-5
50. Ruiz-Ortega, M., V. Esteban, M. Ruperez, E. Sanchez-Lopez, J. Rodriguez-Vita, G. Carvajal & J. Egido: Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens 15, 159-166(2006)
http://dx.doi.org/10.1097/01.mnh.0000203190.34643.d4
PMid:16481883
51. Otani, A., H. Takagi, K. Suzuma & Y. Honda: Angiotensin II potentiates vascular endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res 82, 619-628(1998)
PMid:9529167
52. Matavelli, L. C., J. Huang & H. M. Siragy: (Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. Clin Exp Pharmacol Physiol 37, 277-282(2010)
http://dx.doi.org/10.1111/j.1440-1681.2009.05292.x
PMid:19769609 PMCid:2858767
53. Janka, H. U., J. H. Warram, L. I. Rand & A. S. Krolewski: Risk factors for progression of background retinopathy in long-standing IDDM. Diabetes 38, 460-464(1989)
http://dx.doi.org/10.2337/diabetes.38.4.460
PMid:2647552
54. Teuscher, A., H. Schnell & P. W. Wilson: Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure. Diabetes Care 11, 246-251(1988)
http://dx.doi.org/10.2337/diacare.11.3.246
PMid:3416678
Key Words: Renin-angiotensin system, (Pro)renin receptor, Receptor-associated prorenin system, Age-related macular degeneration, Choroidal neovascularization, Diabetic retinopathy, Diabetic macular edema, Retinal inflammation, Review
Send correspondence to: Susumu Ishida, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Japan, Tel: 81-11-706-5943, Fax: 81-11-706-5948, E-mail:ishidasu@med.hokudai.ac.jp