Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay

Yokota, Harumasa; Mori, Fumihiko; Kai, K; Nagaoka, Taiji; Izumi, Naohiro; Takahashi, Atsushi; Hikichi, Taiichi; Yoshida, Akitoshi; Suzuki, Fujio; Ishida, Yuichi

doi:10.1136/bjo.2004.056580

Cited by 18 publications

(16 citation statements)

References 38 publications

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“…18,25,27,62 Plasma prorenin is increased with the onset of PDR in diabetic patients, 63,64 and serum total renin (prorenin and renin) is two times higher in insulin-dependent diabetic patients than in normal subjects, 65 suggesting that the RAS may be activated in patients with PDR. In diabetic patients with PDR, the prorenin concentrations in vitreous is 100 times the level expected on the basis of the plasma protein content of ocular fluid.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II and Its Receptor Subtypes in the Human Retina

Senanayake

Drazba

Shadrach

et al. 2007

Invest. Ophthalmol. Vis. Sci.

214

156

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PURPOSE.To quantify and evaluate the distribution of angiotensin II (Ang II) and its receptors in the human retina. METHODS. Donor eyes were obtained within 12 hours postmortem and classified as hypertensive or normotensive and diabetic or nondiabetic, based on the donors' medical histories. Ang II in retina and vitreous was quantified by RIA. Ang II receptors were characterized and quantified by competitive membrane-binding assays. Ang II, its heptapeptide metabolite Ang-(1-7), and AT1 and AT2 receptors were localized by immunohistochemistry and confocal imaging. RESULTS. Levels of Ang II in the retina were significantly higher than in vitreous (P Ͻ 0.05). Ang II in the diabetic retina had a higher median compared with that in the nondiabetic retina. Ang II and Ang-(1-7) colocalized in retinal Müller cells. The retina had the highest levels of Ang II receptors that were significantly higher than the optic nerve, retinal pigment epithelium-choroid complex, and ciliary body-iris complex (P Ͻ 0.05). AT1 receptors were more abundant than AT2 receptors in the retina. Immunoreactivity for AT1 was detected in Müller cells and on blood vessels. AT2 receptors were localized throughout the Müller cells and nuclei of ganglion cells and neurons in the inner nuclear layer. CONCLUSIONS. In the human retina, identification of Ang II and its bioactive metabolite Ang-(1-7) in Müller cells suggests that these glial cells are able to produce and process Ang II. Ang receptors were localized in the blood vessels and neural cells. Local Ang II signaling may thus allow for autoregulation of neurovascular activity. Such an autonomous system could modulate the onset and severity of retinovascular disease. (Invest Ophthalmol Vis Sci. 2007;48:3301-3311) DOI:10.1167/iovs.06-1024 D iabetic retinopathy is one of the major complications of diabetes mellitus and the leading cause of visual loss and blindness in the adult population of the United States. It has been viewed as a disorder of the retinal vasculature 1,2 ; however, evidence from numerous reports indicate that neural function of the retina is compromised before the vascular lesions are clinically diagnosed. At the cellular level, diabetes alters the structure and function of most cell types.3-9 Many factors have been implicated in the pathogenesis of diabetic retinopathy. Clinical and experimental studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in the progression of the disease, presumably through local changes in blood flow and production of vascular endothelial growth factor (VEGF 10 -22 ). Furthermore, Ang II may act as an inflammatory agent by enhancing vascular permeability through prostaglandins and VEGF 23 and contribute to the recruitment of inflammatory cells by inducing chemokines and adhesion molecules. 23,24 Although an independent RAS has not been established in the retina, many reports support the concept of a paracrine RAS in this organ. [25][26][27][28] In the classic pathway, Ang II is produced by the sequential processing of plasma...

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Section: Discussionmentioning

confidence: 99%

Angiotensin II and Its Receptor Subtypes in the Human Retina

Senanayake

Drazba

Shadrach

et al. 2007

Invest. Ophthalmol. Vis. Sci.

214

156

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“…Interestingly, high total renin levels have been found in several clinical settings characterized by endothelial dysfunction such as heart failure [34] , preeclampsia [35] , diabetic nephropathy [36][37][38][39] and retinopathy [40][41][42] . Therefore, it is likely that increased total renin levels may also contribute to endothelial dysfunction, a known abnormality in patients with PCOS [43][44][45] .…”

Section: Discussionmentioning

confidence: 99%

Hyperreninemia Characterizing Women with Polycystic Ovary Syndrome Improves after Metformin Therapy

Diamanti-Kandarakis

Economou²,

Livadas³

et al. 2009

Kidney Blood Press Res

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Background: Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation, hyperandrogenemia and insulin resistance. Hyperreninemia is observed in insulin resistance and hyperandrogenemic states. Aims: To investigate the levels of total plasma renin and their possible relationship with insulin resistance and hyperandrogenemia and to explore the effect of metformin on these parameters in PCOS women. Methods: 48 PCOS women who were age- and body mass index (BMI)-matched with 21 healthy women were studied. Total renin, aldosterone levels, glucose and insulin levels were measured at basal state and during an oral glucose tolerance test in all subjects. A subgroup of women with PCOS was evaluated 6 months after metformin administration. Results: Total renin levels were significantly higher in PCOS women compared to controls. PCOS women compared to controls displayed higher areas under the curve for glucose, insulin and total renin (AUCREN). Mean AUCREN was correlated significantly with insulin resistance indices and positively with free testosterone levels. Total renin, aldosterone, androgen levels and insulin sensitivity indices were significantly improved after 6 months on metformin treatment. Conclusions: PCOS women demonstrated an insulin resistance and hyperandogenemia-related increase in serum total renin levels. Metformin treatment was shown to significantly reduce total renin levels.

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“…Normally, prorenin is converted into renin in a proteolytic manner (figure 1a); however, in diabetes, binding of prorenin to the (pro)renin receptor changes its structure and subsequently exposes its active site located in renin in a non-proteolytic manner (figure 1b). 6 This newly identified mechanism of the local RAS is referred to as the receptor-associated prorenin system (RAPS), which has been reported to play a key role in diabetic nephropathy 7 and hypertensive organ damages 8,9 as well as DR. 5 Our previous cross-sectional study demonstrated that serum levels of prorenin in patients with type 2 diabetes increase with the severity of DR, also indicating that prorenin might promote progression of DR. 10 Interestingly, the serum levels of prorenin in patients with diabetes and no DR are significantly higher than those in normal subjects, which might indicate that patients with diabetes with higher serum levels of prorenin may develop DR relatively earlier than patients with relatively lower serum levels of prorenin. Taken together, we speculated that prorenin level increases before DR development and that measuring prorenin might be a way to predict the development of DR. To our knowledge, no study has reported that the serum levels of prorenin increase before the development of DR in patients with type 2 diabetes.…”

Section: Introductionmentioning

confidence: 97%

Higher levels of prorenin predict development of diabetic retinopathy in patients with type 2 diabetes

Yokota

Nagaoka

Tani

et al. 2011

J Renin Angiotensin Aldosterone Syst

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The aim was to determine whether serum prorenin levels affect the development of diabetic retinopathy (DR) in type 2 diabetes. Baseline serum prorenin levels were measured in 196 patients (85 males, 111 females) with type 2 diabetes without DR using the antibody-activating direct prorenin assay. The fundi were checked regularly. The participants were divided into two groups based on the serum prorenin levels (high and low). We used Kaplan-Meyer analysis to detect differences in the development of DR between the two groups within the same gender. Kaplan-Meyer analysis showed that males with a high serum prorenin level tended to develop DR earlier and more frequently than males with a low prorenin level (p = 0.004 by the log rank test). However, there was no difference in the development of DR between high and low groups in females (p = 0.58). Serum prorenin levels in males with type 2 diabetes could be a new prognostic indicator of the development of DR.

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Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay

Cited by 18 publications

References 38 publications

Angiotensin II and Its Receptor Subtypes in the Human Retina

Angiotensin II and Its Receptor Subtypes in the Human Retina

Hyperreninemia Characterizing Women with Polycystic Ovary Syndrome Improves after Metformin Therapy

Higher levels of prorenin predict development of diabetic retinopathy in patients with type 2 diabetes

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