RILLKKMPSV Influences the Vasculature, Neurons and Glia, and (Pro)Renin Receptor Expression in the Retina

Wilkinson-Berka, Jennifer L.; Heine, R.J.; Tan, Genevieve; Cooper, Mark E.; Hatzopoulos, Kate M; Fletcher, Erica L.; Binger, Katrina J.; Campbell, Duncan J.; Miller, Antonia Grace

doi:10.1161/hypertensionaha.109.148221

Cited by 57 publications

(68 citation statements)

References 28 publications

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“…1d-f, f″) and in Müller cells within the inner nuclear layer (Fig. 1d-f), which is consistent with previous reports [14,17,29]. Antibody Ms3-24 also detected a signal in the photoreceptor layer (Fig.…”

Section: Resultssupporting

confidence: 92%

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(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

et al. 2012

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Aims/hypothesis The renin-angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. Methods Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy (PDR) and 16 eyes of controls with non-diabetic, idiopathic macular diseases (macular hole and epiretinal membrane) were collected. Protein levels of soluble (P)RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of (P)RR and related molecules in fibrovascular tissues from PDR eyes. Results (P)RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF). Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by (P)RR or ERK signalling blockade. Proteases known to cleave (P)RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble (P)RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Conclusions/interpretation Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR.

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Section: Resultssupporting

confidence: 92%

“…Endothelial localisation of (P)RR in human PDR fibrovascular tissues (P)RR localisation to retinal vessels was previously demonstrated in rodents [14,17,19,29]; however, no studies on human ocular tissue have been reported. First, we confirmed mRNA expression of (P)RR and RAS compo- (Fig.…”

Section: Resultsmentioning

confidence: 99%

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

et al. 2012

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“…[135][136][137][138][139] Renal juxtaglomerular cells are the only known site of renin production, whereas the kidney and a number of extrarenal tissues, including the adrenal gland, ovary, testis, placenta and retina, produce prorenin. [140][141][142] Plasma prorenin concentrations are 10-20-fold higher than those of rennin.…”

Section: Role Of Renin-ang Aldosterone System With Emphasis On Aldostmentioning

confidence: 99%

“…The finding that PRRB reduced phosphorylated extracellular signal-regulated kinases 1/2 expression in cultured brain capillary endothelial cells stimulated with prorenin, but not in cells stimulated with angiotenin II, was consistent with a specific effect of PRRB on the actions of prorenin. Recently, Wilkinson-Berka et al 136 have reported that a (P)RR antagonist-RILLKKMPSV-clearly exhibited antiangiogenic and anti-inflammatory effects in a model of OIR. However, (P)RR antagonist also compromised the electroretinogram in shams and OIR and increased phosphorylated extracellular signal-regulated kinases 1/2 immunolabeling in shams but not OIR.…”

Section: Role Of Renin-ang Aldosterone System With Emphasis On Aldostmentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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“…Wholemounts of mouse retina were prepared as described previously [3,25]. Briefly, eyes were fixed in 4% paraformaldehyde (wt/vol.)…”

Section: Animals Procedures Complied With the Alfred Medicalmentioning

confidence: 99%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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Aim/hypothesis We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy. Methods Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg −1 day −1 , pump), or diabetic + lisinopril (10 mg kg −1 day −1 , drinking water) rats were evaluated over 16 weeks. For oxygeninduced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg −1 day −1 , pump) or lisinopril (10 mg kg −1 day −1 , drinking water) was administered during retinopathy development between postnatal days 12 and 18. Results Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg −1 day −1 aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg −1 day −1 aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg −1 day −1 aliskiren and normalised by 30 mg kg −1 day −1 aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels. Conclusions/interpretation Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

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RILLKKMPSV Influences the Vasculature, Neurons and Glia, and (Pro)Renin Receptor Expression in the Retina

Cited by 57 publications

References 28 publications

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

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