Involvement of the Rho/Rho Kinase Signaling Pathway in Platelet-Derived Growth Factor BB-induced Vascular Endothelial Growth Factor Expression in Diabetic Rat Retina

Yokota, Tamotsu; Utsunomiya, Kazunori; Taniguchi, Kanta; Gojo, Atsushi; Kurata, Hiroyuki; Tajima, Naoko

doi:10.1007/s10384-007-0471-0

Cited by 39 publications

(25 citation statements)

References 33 publications

(31 reference statements)

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“…This study provided new insight on the role of Rho-kinase, demonstrating that Rho-kinase may regulate intracellular translocation of transcriptional factors, likely through re-organization of actin stress fibers. Finally, we have shown that Rhokinase blockade attenuates other microvascular complications such as diabetic retinopathy [56] and neuropathy [57], as well as atherosclerosis [58]. Importantly, the effect of Rho-kinase inhibitors on diabetic complications is independent of glucose and blood pressure [51,53].…”

Section: Vldl Ldl Idlmentioning

confidence: 92%

Dyslipidemia in diabetic nephropathy

2016

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Diabetic nephropathy (DN) not only is a major cause of end-stage renal disease (ESRD) in developing and developed countries but also plays a critical role as a risk factor for cardiovascular disease. The pathogenesis of DN is multifactorial and remains to be elucidated. It is well known that dyslipidemia is frequently complicated with diabetes. Recently, dyslipidemia has been recognized to be involved in the progression of DN. In general, diabetic dyslipidemia is caused by impaired action of lipoprotein lipase (LPL) that is localized to the endothelial cells, resulting in increased serum levels of increased triglyceride (TG) and decreased high-density lipoprotein cholesterol (HDL-C). Smaller size and modified low-density lipoprotein (LDL), such as glycated and oxidized LDL, play important roles to induce vascular and renal cellular dysfunction. Previous studies demonstrated that dyslipidemia enhances macrophage infiltration and excessive extracellular matrix (ECM) production in the glomeruli under diabetic conditions, leading to the development of DN. Clinical studies have demonstrated that lipid-lowering therapy shows a protective effect on the renal function. It is well known that statins reduce albuminuria in patients with DN. A series of our studies indicated that this effect is mediated by Rho-kinase inhibition. Rho-kinase plays a key role in the pathogenesis of DN by activating the inflammatory pathway, including oxidative stress, NF-κB, and hypoxia inducible factor (HIF)-1. Intriguingly, Rho-kinase inhibitors have been shown to attenuate glomerulosclerosis as well as atherosclerosis. Therefore, Rho-kinase could be a promising therapeutic target for both DN and cardiovascular disease.

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Section: Vldl Ldl Idlmentioning

confidence: 92%

Dyslipidemia in diabetic nephropathy

2016

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“…In this study, ROCK inhibition by ripasudil caused intraretinal vessel growth with reduced neovascular tufts. Because it has been reported that ROCK inhibitor treatment reduced VEGF expression in diabetic retina, 32 ripasidul might modulate VEGF concentration to the appropriate level, which does not affect physiological vascularization, resulting in vascular normalization. 25,26 A ROCK inhibitor, fasudil, has already been shown to improve ischemia in patients with acute ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Yamaguchi

Nakao

Arita

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. In this study, we investigated the therapeutic potential of a Rho-associated coiledcoil-containing protein kinase (ROCK) inhibitor ripasudil (K-115) eye drop on retinal neovascularization and hypoxia.METHODS. In vitro, human retinal microvascular endothelial cells (HRMECs) were pretreated with ripasudil and then stimulated with VEGF. ROCK activity was evaluated by phosphorylation of myosin phosphatase target protein (MYPT)-1. Endothelial migration and cell viability were assessed by cell migration and MTT assay, respectively. The concentration of ripasudil in the retina was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo, normal saline, 0.4%, or 0.8% ripasudil were administered three times a day to mice with oxygen-induced retinopathy (OIR). The areas of neovascularization and avascular retina were also quantified with retinal flat-mounts at postnatal day (P) 15, P17, or P21. The retinal hypoxic area was evaluated using hypoxia-sensitive drug pimonidazole by immunohistochemistry at P17. The vascular normalization was also evaluated by immunohistochemistry at P17. RESULTS.Ripasudil but not fasudil significantly reduced VEGF-induced MYPT-1 phosphorylation in HRMECs at 30 lmol/L. Ripasudil significantly inhibited VEGF-induced HRMECs migration and proliferation. The concentration of ripasudil in the retina was 3.8 to 10.4 lmol/ L and 6.8 to 14.8 lmol/L after 0.4% and 0.8% ripasudil treatment, respectively. In the 0.4% and 0.8% ripasudil treated OIR mice, the areas of neovascularization as well as avascular area in the retina was significantly reduced compared with those of saline-treated mice at P17 and P21. Pimonidazole staining revealed that treatment with 0.4% and 0.8% ripasudil significantly inhibited the increase in the hypoxic area compared with saline. 0.8% ripasudil could cause intraretinal vascular sprouting and increase retinal vascular perfusion.CONCLUSIONS. Novel ROCK inhibitor ripasudil eye drop has therapeutic potential in the treatment of retinal hypoxic neovascular diseases via antiangiogenic effects as well as vascular normalization.

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“…In 1948 Michaelson first suggested the implication of a generic angiogenic factor in the neovascularization process occurring in retinopathy [5]; nowadays several studies stress that a key role in the development of diabetic retinopathy is indeed played by VEGF [6,7]. The expression of VEGF in diabetic retina can be regulated by different pathways, , such as Rho/Rho Kinase, ERK1/2, and Protein Kinase C (PKC) [8][9][10]. PKC is a family of at least 10 serine-threonine kinases ubiquitously expressed and able to participate in multiple cellular functions [11,12].…”

Section: Introductionmentioning

confidence: 99%