The Urokinase Receptor-Derived Peptide UPARANT Recovers Dysfunctional Electroretinogram and Blood–Retinal Barrier Leakage in a Rat Model of Diabetes

Cammalleri, Maurizio; Locri, Filippo; Marsili, Stefania; Monte, Massimo Dal; Pisano, Claudio; Mancinelli, Angelo; Lista, L.; Rusciano, Dario; Rosa, Mario De; Pavone, Vincenzo; Bagnoli, Paola

doi:10.1167/iovs.17-21593

Cited by 15 publications

(50 citation statements)

References 54 publications

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“…UPARANT was cleared from the plasma with a t 1/2 of 2.2 hours in the elimination phase. Control values were in line with a previous work . No differences were found between control and STZ rats.…”

Section: Resultssupporting

confidence: 92%

“…In all experiments, no differences were observed between untreated and vehicle‐treated rats. UPARANT dose and regimen were in line with those used in previous studies . The rats were kept individually in metabolic cages for 24 hours to collect urine for the measurement of urine output.…”

Section: Methodsmentioning

confidence: 99%

“…PK and UPARANT tissue distribution were as previously described . Briefly, for plasma PK, a volume of 0.2 mL blood was extracted at fixed time intervals (0.25, 0.5, 1, 2, 4, 6, 8, 12, 16 and 24 hours after dose) from the femoral vein.…”

Section: Methodsmentioning

confidence: 99%

“…The uPAR‐derived tetrapeptide Ac‐L‐Arg‐Aib‐L‐Arg‐L‐Cα(Me)PheNH 2 (UPARANT, recently designated as Cenupatide in the International Nonproprietary Names nomenclature) has been designed to compete with N‐formyl‐Met‐Leu‐Phe peptide for binding to FPRs . It is endowed with a significant anti‐inflammatory and antiangiogenic activity both in vitro and in vivo and has been shown to protect the retina from pathologic changes induced by diabetic retinopathy (DR) in animal models . In this scenario, the possibility that dysregulated uPAR pathway participates to the pathogenic mechanisms of DN may add further value to the possible development of UPARANT as valuable therapy against diabetes complications.…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

Monte

Cammalleri

Pecci

et al. 2018

J Cellular Molecular Medi

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The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches.

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

Monte

Cammalleri

Pecci

et al. 2018

J Cellular Molecular Medi

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“…As shown by additional findings, UPARANT can be detected in the eye 2 hours after its administration and its delivery to the retina is approximately 15% of that in the eye indicating its ability to cross the BRB and supporting the validity of subcutaneous administration as potentially effective in the treatment of ocular diseases. After 24 hours, UPARANT level in the eye is about 20% of that at 2 hours indicating a half‐life of approximately 10‐11 hours and suggesting a potential long duration of the intraocular pharmacologic effect . UPARANT dose and regimen used here are in line with those used in previous studies in rats in which systemic treatment with the drug was shown both effective and safe …”

Section: Discussionsupporting

confidence: 83%

The urokinase‐type plasminogen activator system as drug target in retinitis pigmentosa: New pre‐clinical evidence in the rd10 mouse model

Cammalleri

Monte

Locri

et al. 2019

J Cellular Molecular Medi

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Retinitis pigmentosa (RP) is characterized by progressive loss of vision due to photoreceptor degeneration leading to secondary inflammation. The urokinase‐type plasminogen activator (uPA) system contributes to retinal inflammation, but its role in RP is unknown. In the rd10 mouse model of RP, we addressed this question with the use of the peptide UPARANT designed to interact with the uPA system. UPARANT was systemically administered from post‐natal day (PD) 10 to PD30 when its efficacy in RP rescue was investigated using electroretinographic recordings, Western blot and immunocytochemistry. Temporal profile of protein expression in the uPA system was also investigated. UPARANT reduced both Müller cell gliosis and up‐regulated levels of inflammatory markers and exerted major anti‐apoptotic effects without influencing the autophagy cascade. Rescue from retinal cell degeneration was accompanied by improved retinal function. No scotopic phototransduction was rescued in the UPARANT‐treated animals as determined by the kinetic analysis of rod‐mediated a‐waves and confirmed by rod photoreceptor markers. In contrast, the cone photopic b‐wave was recovered and its rescue was confirmed in the whole mounts using cone arrestin antibody. Investigation of the uPA system regulation over RP progression revealed extremely low levels of uPA and its receptor uPAR both of which were recovered by HIF‐1α stabilization indicating that HIF‐1 regulates the expression of the uPA/uPAR gene in the retina. Ameliorative effects of UPARANT were likely to occur through an inhibitory action on up‐regulated activity of the αvβ3 integrin/Rac1 pathway that was suggested as a novel target for the development of therapeutic approaches against RP.

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UPARANT is an effective antiangiogenic agent in a mouse model of rubeosis iridis

et al. 2019

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Puncture-induced iris neovascularization (rubeosis iridis; RI) in mice is associated with upregulation of extracellular matrix (ECM) degradation and inflammatory factors. The anti-angiogenic and anti-inflammatory efficacy of UPARANT in reducing RI was determined by noninvasive, in vivo iris vascular densitometry, and confirmed in vitro by quantitative vascular-specific immunostaining. Intravitreal administration of UPARANT successfully and rapidly reduced RI to non-induced control levels. Molecular analysis revealed that UPARANT inhibits formyl peptide receptors through a predominantly anti-inflammatory response, accompanied with a significant reduction in ECM degradation and inflammation markers. Similar results were observed with UPARANT administered systemically by subcutaneous injection. These data suggest that the tetrapeptide UPARANT is an effective anti-angiogenic agent for the treatment of RI, both by local and systemic administrations. The effectiveness of UPARANT in reducing RI in a model independent of the canonical vascular endothelial growth factor (VEGF) proposes an alternative for patients that do not respond to anti-VEGF treatments, which could improve treatment in proliferative ocular diseases. Key messages UPARANT is effective in the treatment of rubeosis iridis, both by local and systemic administrations. UPARANT can reduce VEGF-independent neovascularization. Electronic supplementary material The online version of this article (10.1007/s00109-019-01794-w) contains supplementary material, which is available to authorized users.

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The Urokinase Receptor-Derived Peptide UPARANT Recovers Dysfunctional Electroretinogram and Blood–Retinal Barrier Leakage in a Rat Model of Diabetes

Cited by 15 publications

References 54 publications

Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

The urokinase‐type plasminogen activator system as drug target in retinitis pigmentosa: New pre‐clinical evidence in the rd10 mouse model

UPARANT is an effective antiangiogenic agent in a mouse model of rubeosis iridis

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