Retinal Dysfunction in Diabetic Ren-2 Rats Is Ameliorated by Treatment with Valsartan but Not Atenolol

Phipps, John; Wilkinson-Berka, Jennifer L.; Fletcher, Erica L.

doi:10.1167/iovs.06-0892

Cited by 54 publications

(48 citation statements)

References 56 publications

(56 reference statements)

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“…ACE inhibition and ARB improve aspects of neuronal and glial damage in both situations [42], such as ameliorating losses in the electroretinogram [25,38,43] and neuronal and glial cell degeneration [44][45][46]. Our identification of renin in retinal Müller cells [2] and ganglion cells [3] is suggestive that aliskiren may influence these cell populations.…”

Section: Discussionmentioning

confidence: 97%

“…These findings are consistent with our previous studies in diabetic Ren-2 rats where we compared ARB with the β-blocker, atenolol. Both treatments normalised BP in diabetic Ren-2 rats; however, only ARB reduced retinal vasculopathy and improved the electroretinogram [24,38]. Similar comparisons in OIR may not necessarily be informative given that β-blockers have anti-proliferative effects in OIR [39], and whether this occurs by a BPdependent mechanism is uncertain as BP cannot be measured in P18 rodents.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

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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“…26 Given these findings, it was not surprising that valsartan had no effect on the ERG and p-ERK1/2 in shams and improved p-ERK1/2 in OIR. It might be expected that valsartan would restore the ERG in OIR; however, this was unlikely given that although improvements in individual neuronal and glial cell populations can occur in OIR, recovery of overall retinal function can take much longer than the P18 time frame of the present study.…”

Section: Wilkinson-berka Et Al (Pro)renin Receptor and Retinopathymentioning

confidence: 99%

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

et al. 2010

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Abstract-The (pro)renin receptor [(P)RR] is implicated in organ pathology. We examined the cellular location of the (P)RR and whether a putative (P)RR antagonist, RILLKKMPSV, corresponding to the handle region of the prorenin prosegment (handle region peptide [HRP]) influences angiogenesis, inflammation, and neuronal and glial function in rat retina. The (P)RR was localized to retinal vessels, endothelial cells, and pericytes, but most immunolabeling was in ganglion cells and glia. HRP (1 mg/kg per day by IP injection) reduced physiological angiogenesis in developing retina. Moreover, HRP (0.1 mg/kg per day by subcutaneous minipump) reduced pathological retinal angiogenesis, inflammation, and vascular endothelial growth factor and intercellular adhesion molecule-1 mRNA in rats with oxygen-induced retinopathy (OIR) to an extent similar to valsartan (10 mg/kg per day, IP). In contrast to its effects on vasculature, HRP compromised the electroretinogram in shams and OIR and increased phosphorylated extracellular-signal-related protein kinase 1/2 immunolabeling in shams but not in OIR, whereas valsartan did not affect the electroretinogram and reduced extracellular-signal-related protein kinase 1/2 immunolabeling in OIR. Retinal (P)RR mRNA levels were increased in OIR; HRP, but not valsartan, increased (P)RR mRNA levels in shams, whereas both HRP and valsartan reduced (P)RR mRNA levels in OIR. A control peptide (VSPMKKLLIR, 0.1 mg/kg per day) did not influence retinal vasculopathy or function. Circulating HRP levels in rats administered 1 mg/kg per day HRP were undetectable (Ͻ3 pmol/L). We conclude that HRP had protective effects on the retinal vasculature similar to those of valsartan; however, unlike valsartan, HRP injured neuro-glia, which may involve the (P)RR, although the undetectable circulating HRP level makes a direct effect of HRP on retinal (P)RR function unlikely.

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“…Increasing evidence has suggested the contribution of the RAS to diabetes-induced retinal vascular complications including leukocyte adhesion (4), hyperpermeability (11), and impaired blood flow (12); however, little is known about the pathogenesis of angiotensin II-mediated neuronal dysfunction in the diabetic retina. Although AT1R blockade led to amelioration of hypertension-induced retinal dysfunction that was exacerbated with diabetes (13), no data have been reported that show the direct effect of AT1R signaling on diabetes-induced retinal dysfunction together with underlying molecular mechanisms.…”

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confidence: 99%

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

et al. 2008

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OBJECTIVE-Pathogenic mechanisms underlying diabetesinduced retinal dysfunction are not fully understood. The aim of the present study was to show the relationship of the reninangiotensin system (RAS) with the synaptic vesicle protein synaptophysin and neuronal activity in the diabetic retina.RESEARCH DESIGN AND METHODS-C57BL/6 mice with streptozotocin-induced diabetes were treated with the angiotensin II type 1 receptor (AT1R) blocker telimsartan or valsartan, and retinal function was analyzed by electroretinography. Retinal production of the RAS components and phosphorylation of ERK (extracellular-signal regulated kinase) were examined by immunoblotting. Retinal mRNA and protein levels of synaptophysin were measured by quantitative RT-PCR and immunoblot analyses, respectively. In vitro, synaptophysin levels were also evaluated using angiotensin II-stimulated PC12D neuronal cells cultured with or without the inhibition of ERK signaling or the ubiquitin-proteasome system (UPS).RESULTS-Induction of diabetes led to a significant increase in retinal production of angiotensin II and AT1R together with ERK activation in the downstream of AT1R. AT1R blockade significantly reversed diabetes-induced electroretinography changes and reduction of synaptophysin protein, but not mRNA, levels in the diabetic retina. In agreement with the AT1R-mediated posttranscriptional downregulation of synaptophysin in vivo, in vitro application of angiotensin II to PC12D neuronal cells caused the UPS-mediated degradation of synaptophysin protein via AT1R, which proved to be induced by ERK activation.CONCLUSIONS-These data indicate the first molecular evidence of the RAS-induced synaptophysin degradation and neuronal dysfunction in the diabetic retina, suggesting the possibility of the AT1R blockade as a novel neuroprotective treatment for diabetic retinopathy.

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Retinal Dysfunction in Diabetic Ren-2 Rats Is Ameliorated by Treatment with Valsartan but Not Atenolol

Cited by 54 publications

References 56 publications

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

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

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

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

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