Masako Furukawa

Effect of Exercise on Kidney Function, Oxidative Stress, and Inflammation in Type 2 Diabetic KK-Ay Mice

Exercise is recommended for the management of type 2 diabetes, but its effects on diabetic nephropathy (DN) are still unknown. We hypothesized that appropriate exercise improves early DN via attenuation of inflammation and oxidative damage. Type 2 diabetic KK-A y mice, a spontaneous DN model, underwent two different kinds of exercise (i.e., moderate and low intensity). Sedentary mice or those undergoing an exercise regimen causing no significant body weight loss were used. We examined the urinary excretion of albumin, number of podocytes and macrophages, renal expressions of HIF-1α and MCP-1, and biomarkers of oxidative stress such as urinary 8-OHdG and serum SOD. Exercise reduced urinary levels of albumin and also maintained the number of podocytes in the exercised KK-A y mice independently of improvements of overweight and hyperglycemia, although moderate-intensity exercise increased expression of HIF-1α. Sedentary KK-A y mice showed increased expression of MCP-1 and infiltration of macrophage, increased urinary 8-OhdG, and decreased serum SOD levels compared with exercised KK-A y mice. On the whole, low-intensity exercise attenuates progression of early DN without affecting marked renal ischemia. Reduction rates of urinary albumin and maintained podocyte numbers, with parallel improvements in oxidative damage and inflammation, are related to beneficial effects of exercise in diabetic kidney disease.

Risk factors associated with increased left ventricular mass index in chronic kidney disease patients evaluated using echocardiography

BACKGROUND It is still not clear which factors are associated with left ventricular mass index (LVMI) in chronic kidney disease (CKD) patients, based on the patients physical and biochemical parameters at the time of echocardiography. The objective of the present study was to identify factors associated with LVMI in CKD patients (predialysis patients), using echocardiography. METHODS Physical, biochemical and LVMI data evaluated by echocardiography were retrospectively analyzed in 930 CKD patients in Juntendo University Hospital, Tokyo, Japan. RESULTS Levels of systolic blood pressure (SBP) and hemoglobin (Hb) were independent risk factors for increased LVMI in multivariate regression analysis. SBP was significantly correlated with LVMI (r=0.314, p<0.0001). The level of Hb was inversely correlated with LVMI (r=-0.372, p<0.0001). LVMI increased with decreasing renal function. SBP was significantly higher in patients with left ventricular hypertrophy (LVH) in CKD stages 2 and 5, and Hb was significantly lower in patients with LVH in stages 4 and 5 than in the group without LVH. CONCLUSIONS It is important to treat hypertension and anemia to prevent LVH in CKD patients. These findings have some therapeutic implications for treatment strategies for predialysis patients.

Pathogenesis and Novel Treatment from the Mouse Model of Type 2 Diabetic Nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide. However, current treatments remain suboptimal. Many factors, such as genetic and nongenetic promoters, hypertension, hyperglycemia, the accumulation of advanced glycation end products (AGEs), dyslipidemia, and albuminuria/proteinuria itself, influence the progression of this disease. It is important to determine the molecular mechanisms and treatment of this disease. The development of diabetes results in the formation of AGEs, oxidative stress, and the activation of the renin-angiotensin-aldosterone system (RAAS) within the kidney, which promotes progressive inflammation and fibrosis, leading to DN and declining renal function. A number of novel therapies have also been tested in the experimental diabetic model, including exercise, inhibitors of the RAAS (angiotensin type 1 receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors), inhibitors of AGE (pyridoxamine), peroxisome proliferator-activated receptor (PPAR) γ agonists (pioglitazone), inhibitors of lipid accumulation (statins and eicosapentaenoic acid (EPA)), and the vitamin D analogues. This review summarizes the advances in knowledge gained from our studies and therapeutic interventions that may prevent this disease.

Predictive factors associated with left ventricular hypertrophy at baseline and in the follow-up period in non-diabetic hemodialysis patients.

Hemodialysis (HD) patients frequently have an elevated left ventricular mass index (LVMI). Currently, left ventricular (LV) hypertrophy and dysfunction are considered to be the strongest predictors of cardiovascular mortality in dialysis patients. The objectives of the present study are to investigate the factors associated with elevated LVMI and to discuss therapeutic implications for the treatment strategy for pre‐dialysis and HD patients. The correlation among biochemical values, physical specimens, and LVMI using echocardiography was prospectively analyzed in 30 non‐diabetic HD patients in the Juntendo University Hospital. Measurement of these parameters was performed at 0, 12, and 24 months after initiation of HD. Systolic blood pressure (SP), human atrial natriuretic peptide (hANP), and hemoglobin (Hb) levels were significantly correlated with LVMI. SBP, residual glomerular filtration rate (rGFR), and serum albumin levels were identified as independent risk factors for LVMI in multivariate regression analysis at initiation of HD. SBP, hANP, and Hb levels were identified as independent risk factors for LVMI in multivariate regression analysis after 24 months. SBP, rGFR, and serum albumin levels were predictive factors for LVMI at initiation of HD. SBP, hANP, and Hb levels were also predictive factors for LVMI after initiation of HD.

Predictive Factors Associated with the Period of Time before Initiation of Hemodialysis in CKD Stages 4 and 5

Background: A majority of patients with chronic kidney disease (CKD) have cardiovascular disease at the initiation of dialysis therapy, suggesting that periodic echocardiographic examinations are important in such patients. The purpose of the present study was to evaluate the correlation between echocardiographic parameters and period of time before initiation of hemodialysis (iHD) in patients with CKD. Methods: 140 patients with CKD stages 4 and 5 were enrolled. They were divided into diabetes and nondiabetes groups. Cardiac predictive parameters for the period of time before iHD were investigated in the patients using univariate and multivariate regression analyses. Results: In the nondiabetes group, systolic blood pressure (SBP) and left atrial volume index (LAVi) were identified as independent risk factors for the period of time before iHD by multivariate regression analysis. Serum albumin level was identified as an independent risk factor in the diabetes group. SBP, LAVi and serum albumin level were identified as independent risk factors in the combined diabetes and nondiabetes groups. Conclusion: LAVi measurements during echocardiography, together with SBP and serum albumin levels, may be useful predictive factors for the period of time before iHD in patients with CKD stages 4 and 5.

Predictive factors associated with change rates of LV hypertrophy and renal dysfunction in CKD patients

BACKGROUND This longitudinal study is the first report on the factors associated with change rates of the estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) using echocardiography in chronic kidney disease (CKD) patients. METHODS Measurements of biochemical and physical values, and LVMI evaluated by echocardiography were performed twice (baseline and follow-up period) in pre-dialysis CKD patients. Blood and urine samples were collected at the time of the echocardiographic study. RESULTS The change rates of hemoglobin (Hb) and transferrin saturation (TSAT: (serum iron/total iron binding capacity)) were identified as independent risk factors for changes in eGFR by multivariate regression analysis. In the LVMI improvement group, the change rate of systolic blood pressure (sBP) was identified as an independent factor for change in LVMI. In the LVMI worsening group, the change rates of sBP, proteinuria and Hb were identified as independent risk factors for changes in LVMI. CONCLUSIONS It appears that treatment of renal and iron deficiency anemia might prevent progression of renal dysfunction. To prevent LV hypertrophy in CKD patients, renal anemia, hypertension and proteinuria should be treated.

Identification of quantitative trait loci for diabetic nephropathy in KK-Ay/Ta mice.

BACKGROUND The pathogenesis and development of human diabetic nephropathy involves genetic factors. Since human diabetic nephropathy is a heterogeneous disorder, identification of responsible gene loci is difficult. We studied candidate gene loci for diabetic nephropathy, using quantitative trait locus (QTL) analysis of a spontaneous animal model for diabetic nephropathy: KK-Ay/Ta × normal BALB/cA F2 intercross mice. METHODS We examined 270 (KK-Ay/Ta × BALB/cA) F2 intercross mice for their urinary albumin to creatinine ratios (ACRs), HbA1c and fasting body weights (FBW) at 8, 12, 16 and 20 weeks. Genotypes were investigated using 86 microsatellite markers with QTL analysis. RESULTS ACR in mice at 20 weeks and ACR gain showed a suggestive linkage to chromosome 9 (log of the odds [LOD] scores: 3.8 and 3.4, respectively; designated ACR-1). Gene loci contributing to HbA1c indicated a significant linkage to chromosome 7 (LOD: 5.8 and 8.9) in mice at 8 and 20 weeks (designated HbA1c-1), and FBW indicated a significant linkage to chromosome 1 (LOD: 5.5 and 5.2) in mice at 8 and 12 weeks (designated Fbw-1). At 20 weeks, glomerular to Bowmans capsule volume (G/B) ratio of F2 mice homozygous BB for D9Mit66 was significantly higher than that in homozygous KK and heterozygous KB F2 progeny. The sizes of pancreatic islets in F2 progeny homozygous KK and heterozygous KB for D7Mit100 were larger than those in homozygous BB F2 progeny. CONCLUSION QTL analysis of KK-Ay/Ta mice revealed several new loci contributing to diabetic nephropathy and related phenotypes. Thus, it appears that type 2 diabetes and nephropathy of KK-Ay/Ta mice have different genetic factors.

Effect of the Direct Renin Inhibitor Aliskiren on Urinary Albumin Excretion in Spontaneous Type 2 Diabetic KK-A (y) Mouse.

Objective. Although angiotensin II-mediated inflammation and extracellular matrix accumulation are considered to be associated with the progression of diabetic nephropathy, these processes have not yet been sufficiently clarified. The objective of this study was to determine whether the correction of the abnormal renal expression of MMPs and its inhibitors (MMPs/TIMPs) and cytokines following the administration of aliskiren to KK-A y mice results in a renoprotective effect. Methods. KK-A y mice were divided into two groups, that is, untreated (saline) and treated (aliskiren) groups. Systolic BP, HbA1c levels, and the albumin-creatinine ratio (ACR) were measured. The renal expression of MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (pro)renin receptor ((P)RR) was examined using real-time PCR and/or immunohistochemical staining. Renal MAPK and NF-κB activity were also examined by Western blot analyses and ELISA, respectively. Results. Significant decreases in systolic BP and ACR levels were observed in treated KK-A y mice compared with the findings in untreated KK-A y mice. Furthermore, increases in MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (P)RR expression, in addition to MAPK and NF-κB activity, were significantly attenuated by aliskiren administration. Conclusions. It appears that aliskiren improves albuminuria and renal fibrosis by regulating inflammation and the alteration of collagen synthesis and degradation.