Eisuke Ishizaki

Involvement of Angiotensin II-Dependent Vascular Endothelial Growth Factor Gene Expression via NADPH Oxidase in the Retina in a Type 2 Diabetic Rat Model

Purpose: To clarify the involvement of angiotensin II-dependent vascular endothelial growth factor (VEGF) via NADPH oxidase in the retina in spontaneously diabetic Torii (SDT) rats, a type 2 diabetic rat model. In SDT rats, the plasma glucose level and angiotensin-converting enzyme (ACE) levels were measured, and effects of angiotensin II receptor blocker (ARB) and angiotensin II were also studied. Materials and Methods: We evaluated the age-dependent changes in the peripheral and ocular angiotensin II-forming systems in SDT rats at 15 (n = 8), 20 (n = 8), 30 (n = 7), and 50 weeks of age (n = 8). We also evaluated the effect of an ARB (2.5 mg/kg/day candesartan) or angiotensin II (500 ng/kg/min) on retinal gene expressions of VEGF and p22phox, a subunit of NADPH oxidase. Results: The plasma glucose level was significantly increased from 20 weeks of age. No significant changes in ACE activities in the plasma, aorta, and eye were observed until 30 weeks of age. At 50 weeks, ACE activity in the eyes was significantly increased, whereas ACE activities in the plasma and aorta were not. At 50 weeks, significant increases in VEGF and p22phox, an NADPH oxidase subunit, were significantly reduced by candesartan. Angiotensin II infusion resulted in significant increases in VEGF and p22phox levels. Conclusions: Angiotensin II is involved in the gene expression of VEGF via NADPH oxidase in the retina of SDT rats.

Relationship between Diabetic Macular Edema and Peripheral Th1/Th2 Balance

Purpose: To determine whether inflammatory reactions are involved in the pathogenesis of diabetic macular edema, we examined the relationship between diabetic macular edema and the ratio of T helper 1 (Th1) to T helper 2 (Th2) cells. Methods: Thirty-nine diabetic patients with diabetic retinopathy were evaluated at our hospital between February 2004 and February 2005. Blood samples were collected from each patient, and the ratio of CD4+ Th1 to Th2 cells (Th1/Th2) was determined by flow cytometry after fluorescent antibody staining for intracellular cytokines. Logistic regression analysis was used to determine the association of macular edema with age, gender, HbA1c level, interval after retinal photocoagulation and Th1/Th2 ratios. Differences in these parameters were also compared between patients with and without macular edema. Results: Logistic regression analysis showed that the Th1/Th2 ratios were significantly associated with macular edema (odds ratio = 0.838; p = 0.02), while other variables were not. The Th1/Th2 ratio was significantly lower in the patients with diabetic macular edema than in those without (p = 0.02; t test). Higher Th1/Th2 ratios tended to be associated with better visual acuity. Conclusions: Shifts in the balance of Th1/Th2 towards a predominance of Th2 may represent an exacerbating factor for diabetic macular edema, although a causal relationship has still not been definitively determined.

Progression of nuclear sclerosis based on changes in refractive values after lens-sparing vitrectomy in proliferative diabetic retinopathy

Background Nuclear sclerosis (NS) based on the Emery–Little classification and refractive values after lens-sparing vitrectomy was compared between proliferative diabetic retinopathy (DR) patients and nondiabetic patients. Methods Progression of NS based on the Emery–Little classification and changes in refractive values were compared between 13 proliferative DR patients (14 eyes, DR group) and 14 nondiabetic patients (14 eyes, non-DR group) who underwent lens-sparing vitrectomy. All patients revealed grade I NS based on the Emery–Little classification. Mean patient age and refractive value just after surgery were 56.07 years and −0.33 diopters (D) in the DR group, and 57.06 years and −0.96 D in the non-DR group. Results The Emery–Little classification in the DR group at 6 and 24 months postoperative were grade I (13 eyes)/grade II (one eye) and grade I (eleven eyes)/grade II (three eyes), respectively. Mean refractive values in the DR group at 6, 12, and 24 months postoperative were +0.28 D, +0.27 D, and +0.37 D, respectively. The Emery–Little classification in the non-DR group at 6 and 24 months (or preoperative for patients undergoing cataract surgery) were grade I (five eyes)/grade II (eight eyes) and grade I (zero eyes)/grade II (eight eyes)/grade III (five eyes), respectively. The mean refractive value in the non-DR group at 6 months postoperative was −3.20 D. All eyes exhibited myopic changes and progression of NS. Conclusion The findings of this study show that the progression of NS postvitrectomy is mild, even for DR patients 50 years of age or older, thus suggesting the need to reconsider the indications for simultaneous cataract surgery with vitrectomy.

A case of Alagille syndrome complicated by intraocular lens subluxation and rhegmatogenous retinal detachment.

This case report describes a case of Alagille syndrome with developing intraocular lens subluxation and rhegmatogenous retinal detachment 4 years after cataract surgery. A 15-year-old female patient with Alagille syndrome-associated cataracts in both eyes underwent phacoemulsification aspiration and intraocular lens implantation. Four years postoperative, intraocular lens subluxation developed in her left eye. For treatment, extraction of the dislocated intraocular lens, anterior vitrectomy, and intraocular lens fixation was performed. Three weeks later, the patient developed rhegmatogenous retinal detachment, which was well-treated by pars plana vitrectomy. Cataract surgery needs to be performed carefully in patients with Alagille syndrome due to the weakness of the zonule of Zinn. Careful postoperative observation is necessary for patients with Alagille syndrome who have undergone intraocular surgery in order to facilitate early detection of a possible rhegmatogenous retinal detachment.

Purinergic Vasotoxicity: Role of the Pore/Oxidant/KATP Channel/Ca2+ Pathway in P2X7-Induced Cell Death in Retinal Capillaries

P2X7 receptor/channels in the retinal microvasculature not only regulate vasomotor activity, but can also trigger cells in the capillaries to die. While it is known that this purinergic vasotoxicity is dependent on the transmembrane pores that form during P2X7 activation, events linking pore formation with cell death remain uncertain. To better understand this pathophysiological process, we used YO-PRO-1 uptake, dichlorofluorescein fluorescence, perforated-patch recordings, fura-2 imaging and trypan blue dye exclusion to assess the effects of the P2X7 agonist, benzoylbenzoyl-ATP (BzATP), on pore formation, oxidant production, ion channel activation, [Ca2+]i and cell viability. Experiments demonstrated that exposure of retinal microvessels to BzATP increases capillary cell oxidants via a mechanism dependent on pore formation and the enzyme, NADPH oxidase. Indicative that oxidation plays a key role in purinergic vasotoxicity, an inhibitor of this enzyme completely prevented BzATP-induced death. We further discovered that vasotoxicity was boosted 4-fold by a pathway involving the oxidation-driven activation of hyperpolarizing KATP channels and the resulting increase in calcium influx. Our findings revealed that the previously unappreciated pore/oxidant/KATP channel/Ca2+ pathway accounts for 75% of the capillary cell death triggered by sustained activation of P2X7 receptor/channels. Elucidation of this pathway is of potential therapeutic importance since purinergic vasotoxicity may play a role in sight-threatening disorders such as diabetic retinopathy.

Senior-loken syndrome complicated with severe coats disease-like exudative retinopathy.

BACKGROUND Senior-Loken syndrome is a rare disorder that combines juvenile nephronophthisis with retinitis pigmentosa. METHODS Case report. RESULTS A 9-year-old Japanese girl diagnosed with Senior-Loken syndrome subsequently developed severe Coats disease-like exudative retinopathy. Although retinal coagulation, pars plana lensectomy, and vitrectomy were performed, she lost light perception in both eyes. CONCLUSION Faulty vascular morphogenesis and its dysfunction might contribute to the development of Coats disease-like exudative retinopathy in Senior-Loken syndrome.