All-trans retinoic acid suppresses bone morphogenetic protein 4 in mouse diabetic nephropathy through a unique retinoic acid response element.

Diabetic nephropathy (DN) causes mesangial matrix expansion, which results in glomerulosclerosis and renal failure. Collagen IV (COL4) is a major component of the mesangial matrix that is positively regulated by bone morphogenetic protein 4 (BMP4)/suppressor of mothers against decapentaplegic (Smad1) signaling. Because previous studies showed that retinoids treatment had a beneficial effect on kidney disease, we investigated the therapeutic potential of retinoids in DN, focusing especially on the regulatory mechanism of BMP4. Diabetes was induced with streptozotocin in 12-wk-old male Crl:CD1(ICR) mice, and, 1 mo later, we initiated intraperitoneal injection of all-trans retinoic acid (ATRA) three times weekly. Glomerular matrix expansion, which was associated with increased BMP4, phosphorylated Smad1, and COL4 expression, worsened in diabetic mice at 24 wk of age. ATRA administration alleviated DN and downregulated BMP4, phosopho-Smad1, and COL4. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor-α (RARα) agonist significantly decreased BMP4 and COL4 expression. Genomic analysis suggested two putative retinoic acid response elements (RAREs) for the mouse Bmp4 gene. Chromatin immunoprecipitation analysis and reporter assays indicated a putative RARE of the Bmp4 gene, located 11,488-11,501 bp upstream of exon 1A and bound to RARα and retinoid X receptor (RXR), which suppressed BMP4 expression after ATRA addition. ATRA suppressed BMP4 via binding of a RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice. These findings provide a novel regulatory mechanism for treatment of DN.

Urinary type IV collagen excretion is involved in the decline in estimated glomerular filtration rate in the Japanese general population without diabetes: A 5-year observational study.

Urinary type IV collagen (U-Col4) and albumin excretion is evaluated to monitor the development of diabetic kidney disease. However, U-Col4 excretion in the general population without diabetes has not yet been fully elucidated. In this study, 1067 participants without diabetes and with urinary albumin-creatinine ratio <300 mg/gCr (normo- or microalbuminuria) who underwent an annual health examination in 2004 were enrolled and observed for 5 years. They were divided according to the amount of U-Col4 or urinary albumin excreted. The decline in estimated glomerular filtration rate (eGFR) was calculated. In participants with eGFR ≥80 mL/min, abnormal U-Col4 excretion was indicated as a significant independent risk factor for 10% eGFR change per year, which is one of the prognostic factors for the development of end-stage kidney disease. Moreover, in contrast to urinary albumin excretion, U-Col4 excretion was not related to age or kidney function, suggesting that some individuals with abnormal U-Col4 excretion can have an independent hidden risk for the development of kidney dysfunction. In conclusion, it is important to measure U-Col4 excretion in the general population without diabetes to determine changes in renal features in every individual and help detect future complications such as diabetic kidney disease. If U-Col4 excretion is abnormal, kidney manifestation should be carefully followed up, even if the kidney function and urinalysis findings are normal.

Urinary IgG4 and Smad1 Are Specific Biomarkers for Renal Structural and Functional Changes in Early Stages of Diabetic Nephropathy.

Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (eGFR) >60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower eGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion-both classic pathological findings in DN. Baseline eGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of eGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes.

Implications of Albumin Leakage for Survival in Maintenance Hemodialysis Patients: A 7-year Observational Study.

Albumin leakage during hemodialysis (HD) presents a clinical dilemma. However, protein-binding uremic toxins are suggested to be responsible for increased mortality. No one has investigated the relationship between albumin leakage and mortality. Therefore, the purpose of this observational study was to analyze the association of albumin leakage with mortality in 690 HD patients who survived one year after enrollment. They were divided to three groups who received HD with large (3 g or more per HD session), middle (1 to 3 g) or small (less than 1 g) amount of albumin leakage, respectively. A propensity score analysis minimizing indication bias was performed. Consequently, in a 7-year observation period, 212 patients died. Albumin leakage 3 g or more per HD session provided better prognosis than albumin leakage less than 3 g per HD session. In conclusion, clinically acceptable large albumin leakage provides beneficial effects on mortality in maintenance HD patients.

Plasma adiponectin levels predict cardiovascular events in the observational Arita Cohort Study in Japan: the importance of the plasma adiponectin levels.

As the plasma level of adiponectin is related to metabolic syndrome and cardiovascular events, a low plasma adiponectin level may either cause or trigger cardiovascular disorders. The purpose of this study was to determine whether a low adiponectin level contributes to cardiovascular events, and to investigate the factors influencing adiponectin in the Japanese Arita-cho cohort study.We followed about 2000 subjects in Arita-cho, Saga, Japan as a cohort study, and we enrolled 637 subjects (205 men; 65.1±8.3 years old) who participated in annual health checks from 2005 to 2008 and underwent measurement of the plasma adiponectin level and an oral glucose tolerance test. We monitored the incidence of cardiovascular or cerebrovascular events in these subjects until the end of 2010, discontinuing follow-up at 3 years after the start of enrollment. Subjects with low plasma adiponectin levels (<10.5 ng ml(-1)) had a higher incidence of newly diagnosed cardiovascular diseases such as acute heart failure or acute myocardial infarction than those with high plasma adiponectin levels (≥10.5 ng ml(-1)) over an average of 2.95 years of follow-up. Multivariate analysis showed that the adiponectin level was predicted by the following parameters in all subjects: age (ß=0.16), male gender (ß=-0.267), homeostasis model assessment of insulin resistance (ß=-0.140) and the plasma levels of high-density lipoprotein cholesterol (ß=0.104), uric acid (ß=-0.13), triglycerides (ß=-0.169) and brain natriuretic peptide (ß=0.151). The difference in plasma glucose before and 120 min after the intake of a 75-g glucose load did not influence the plasma adiponectin level. The plasma adiponectin level is useful for predicting cardiovascular events, and is a measure of the risk of lifestyle-related diseases.