ONO-1301, a Sustained-Release Prostacyclin Analog, Ameliorates the Renal Alterations in a Mouse Type 2 Diabetes Model Possibly Through Its Protective Effects on Mesangial Cells

Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-β1, α-smooth muscle actin (α-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-β, type IV collagen, α-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells

Immunohistochemistry of Vasohibin-2 in Human Kidney Disease : Implications in Impaired Glucose Tolerance and Reduced Renal Function

Several angiogenesis-related factors are known to play important roles in the pathogenesis of kidney disease. Vasohibin-2 (VASH-2) was recently reported as a novel proangiogenic factor. Although VASH-2 was demonstrated to accelerate tumor angiogenesis, its roles in non-tumor processes including renal disease have not been well elucidated yet. Here, we performed a retrospective study including an immunohistochemical analysis of human kidney biopsy specimens from 82 Japanese patients with a variety of kidney diseases, and we evaluated the correlations between the immunoreactivity of VASH-2 and the patients’ clinicopathological parameters. VASH-2 immunoreactivity was detected in varying degrees in renal tubules as well as in peritubular capillaries and vasa recta. The cortical and medullary tubule VASH-2+ scores were correlated with the presence of hypertension, and the medullary tubule VASH-2+ score was significantly correlated with the blood glucose (p=0.029, r=0.35) and hemoglobin A1c levels (p=0.0066, r=0.39). Moreover, decreased VASH-2+ scores in the vasa recta were associated with reduced renal function (p=0.0003). These results suggest that VASH-2 could play an important role in the pathogenesis of renal diseases, and that VASH-2 is closely associated with hypertension and impaired glucose tolerance

Renal Distribution of Vasohibin-1 in Patients with Chronic Kidney Disease

Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r＝0.48, p＝0.001) or cortex (r＝0.64, p＜0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r＝0.34, p＝0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r＝0.44, p＝0.01) or medulla (r＝0.63, p＝0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2

IgA Nephropathy Complicated with X-linked Thrombocytopenia

Renal involvement is occasionally observed in Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). It has been reported that galactose-deficient IgA is a closely linked to IgA nephropathy (IgAN), suggesting that patients with XLT/WAS associated with reduced galactosylation on serum IgA are susceptible to IgAN. It is necessary to pay more attention to patients with IgAN due to the potential complication with XLT/WAS. We here present a patient of XLT complicated with mild IgAN who underwent tonsillectomy combined with steroid pulse therapy to achieve complete clinical remission

Exacerbation of diabetic renal alterations in mice lacking vasohibin-1

Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1(+/-)) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1(+/-) mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickening and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31(+) endothelial area was also increased in the diabetic VASH1(+/-) mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy

Shorter dialysis session length was not associated with lower mental health and physical functioning in elderly hemodialysis patients: Results from the Japan Dialysis Outcome and Practice Patterns Study (J-DOPPS)

<div><p>Background</p><p>Health-related quality of life (HRQOL) is often prioritized over long-term survival in elderly patients. Although a longer dialysis session length (DSL) has been shown to reduce mortality, its effects on improving the HRQOL are unknown.</p><p>Methods</p><p>Using data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS), patients aged ≥ 65 years on maintenance hemodialysis were enrolled. DSL was categorized as short (<210 minutes), medium (210–240 minutes), or long (>240 minutes). The primary outcomes were changes in mental health (ΔMH) and physical functioning (ΔPF) scores assessed using the Japanese version of SF-12, in one year. The differences in the ΔMH and ΔPF among the three groups were assessed via regression (beta) coefficients derived using a linear regression model.</p><p>Results</p><p>Of 1,187 patients at baseline, 319 (26.9%) had a short length, 686 (57.8%) a medium length, and 182 (15.3%) a long length. We assessed the ΔMH data from 793 patients and the ΔPF data from 738. No significant differences in the ΔMH were noted for the short or long groups compared with the medium group (score difference: 0.26, 95% confidence interval [CI]: -4.17 to 4.69 for short; score difference: -1.15, 95% CI: -6.17 to 3.86 for long). Similarly, no significant differences were noted for these groups versus the medium group in ΔPF either (score difference: -1.43, 95% CI: -6.73 to 3.87 for short; score difference: -1.71, 95% CI: -7.63 to 4.22 for long).</p><p>Conclusions</p><p>A shorter DSL might have no adverse effects on MH or PF for elderly patients.</p></div

Association between dialysis session length and change in mental health or physical functioning at one year after study initiation.

<p>Association between dialysis session length and change in mental health or physical functioning at one year after study initiation.</p