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Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D™ is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease., (© The Author(s) 2015.)

Objective: To improve prognosis, it is important to predict the incidence of renal failure and cardiovascular disease in type 2 diabetic patients before the progression to advanced nephropathy. We investigated the predictive effects of urinary liver-type fatty acid-binding protein (L-FABP), which is associated with renal tubulointerstitial damage, in renal and cardiovascular prognosis., Research Design and Methods: Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and without overt proteinuria were enrolled between 1996 and 2000 and followed up until 2011. Baseline urinary L-FABP was measured with an enzyme-linked immunosorbent assay. The primary end points were renal and cardiovascular composites (hemodialysis, myocardial infarction, angina pectoris, stroke, cerebral hemorrhage, and peripheral vascular disease). The secondary renal outcomes were the incidence of a 50% decline in estimated glomerular filtration rate (eGFR), progression to an eGFR <30 mL/min/1.73 m(2), and the annual decline rate in eGFR., Results: During a 12-year median follow-up, 103 primary end points occurred. The incidence rate of the primary end point increased in a stepwise manner with increases in urinary L-FABP. In Cox proportional hazards analysis, the adjusted hazard ratio in patients with the highest tertile of urinary L-FBAP was 1.93 (95% CI 1.13-3.29). This relationship was observed even when analyzed separately in normoalbuminuria and microalbuminuria. Patients with the highest tertile of urinary L-FABP also demonstrated a higher incidence of the secondary renal outcomes., Conclusions: Our results indicate that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type 2 diabetic patients without advanced nephropathy.

Fructose induces several kinds of human metabolic disorders; however, information regarding fructose-induced kidney injury is still limited. This study examined fructose-induced kidney injury in mice and clarified the differential susceptibility of three mouse strains: C57Bl/6J, CBA/JN and DBA/2N. In this study all mice were fed with an equal calorie count for sixteen weeks to remove the influence of total energy intake from metabolic effects by fructose-feeding. Only DBA/2N mice, but not C57Bl/6J and CBA/JN mice, fed with fructose displayed tubulointerstitial fibrosis localized on the outer cortex of the kidney together with the increase of mRNA expression of Kim1 and Ngal in the absence of distinct glomerular lesions and albuminuria - decidedly different from diabetic nephropathy. In time-course study of DBA/2N mice fed with fructose diet, the inflammation and fibrosis in the outer cortex of the kidney were enhancing after eight weeks, in parallel with the accumulation of oxidative stress. This progression of renal damage in DBA/2N mice was accompanied with increasing mRNA expression of GLUT5. These results suggest that the responsiveness of GLUT5 expression to fructose at the kidney is one of pivotal roles for the progression of fructose-induced kidney injury., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objectives: This study investigated whether the slope of estimated GFR is different between nonproteinuric subjects with and without diabetes, and what clinical factors are associated with the GFR slope., Design, Setting, Participants, & Measurements: An observational cohort study was performed in 923 subjects, and the predictive value of baseline variables on the GFR slope was investigated., Results: On the basis of the median 3-yr follow-up and 7 measurements of GFR, GFR slope (%/yr, median and interquartile range) was significantly larger in subjects with diabetes (-2.39 (-4.86 to 0.15), n=729) than in those without diabetes (-1.02 (-4.28 to 1.37), n=194), and this difference remained significant with or without presence of hypertension. After adjustments for confounding factors, predictors of GFR decline were found to be baseline high values of glycosylated hemoglobin A1C(HbA1C), GFR, systolic blood pressure, and low plasma total protein in subjects with diabetes, whereas only the latter two were significant in subjects without diabetes. In subjects with diabetes, the high GFR was accounted for by high HbA1C at baseline, and the predictors of GFR decline differed between those with and without hypertension, or with high and low baseline GFR. Any combination of the predictors showed increased risk for GFR decline., Conclusions: GFR slope is substantially affected by multiple factors at various stages. The degree of chronic hyperglycemia is likely to play a crucial role in elevating GFR and accelerating the decline in patients with type 2 diabetes even from the normoalbuminuric stage.

Metabolic syndrome is associated with increased risk of chronic kidney disease, and the renal injury in patients with metabolic syndrome may be a result of altered renal lipid metabolism. We fed wild-type or insulin-sensitive heterozygous peroxisome proliferator-activated receptor gamma-deficient (PPARgamma(+/-)) mice a high-fat diet for 16 weeks. In wild-type mice, this diet induced core features of metabolic syndrome, subsequent renal lipid accumulation, and renal injury including glomerulosclerosis, interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated, determined by increased renal mRNA expression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase (ACC) and by increased ACC activity. In addition, renal lipolysis was suppressed, determined by reduced mRNA expression of the lipolytic enzyme carnitine palmitoyl acyl-CoA transferase 1 and by reduced activity of AMP-activated protein kinase. In PPARgamma(+/-) mice, renal injury, systemic metabolic abnormalities, renal accumulation of lipids, and the changes in renal lipid metabolism were attenuated. Thus, a high-fat diet leads to an altered balance between renal lipogenesis and lipolysis, subsequent renal accumulation of lipid, and renal injury. We suggest that renal lipid metabolism could serve as a new therapeutic target to prevent chronic kidney disease in patients with metabolic syndrome.

Aims/Introduction: Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods: Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results: The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (<30 mL/min/1.73 m2) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age‐dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. Conclusions: During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity‐ and high age‐related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Teneligliptin is a novel oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Safety and efficacy of teneligliptin have been demonstrated in clinical studies; however, data supporting its use in patients with moderate or severe renal impairment are limited. This interim analysis of a post-marketing surveillance of teneligliptin, exploRing the long-term efficacy and safety included cardiovascUlar events in patients with type 2 diaBetes treated bY teneligliptin in the real-world (RUBY), aims to verify the long-term safety and efficacy of teneligliptin in Japanese patients with T2DM and impaired renal function.Methods: For this analysis, we used the data from case report forms of the RUBY surveillance between May 2013 and June 2017. The patients were classified into G1-G5 stages of chronic kidney disease according to estimated glomerular filtration rate (eGFR) at initiation of teneligliptin treatment. Safety and efficacy were evaluated in these subgroups. Patients on dialysis were also assessed. Safety was assessed from adverse drug reactions (ADRs). Glycemic control was evaluated up to 2 years after teneligliptin initiation.Results: A total of 11,677 patients were enrolled in the surveillance and 11,425 patient case-report forms were collected for the interim analysis. The incidence of ADRs in each subgroup was 2.98-6.98% of patients, with no differences in the ADR profile (including hypoglycemia and renal function ADRs) between subgroups. At 1 and 2 years after starting teneligliptin, the least-squares mean change in HbA1c adjusted to the baseline was − 0.68 to − 0.85% and − 0.71 to − 0.85% across the eGFR groups, respectively. Treatment with teneligliptin in patients on dialysis reduced or tended to reduce glycated albumin levels [− 2.29%, (p < 0.001) after 1 year; − 1.64%, (p = 0.064) after 2 years].Conclusions: During long-term treatment, teneligliptin was generally well tolerated in patients with any stage of renal impairment from normal to end-stage renal disease, including those on dialysis, and improved glycemic control.Trial Registration Number: Japic CTI-153047.Funding: Mitsubishi Tanabe Pharma Corporation and Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

Kidney fibrosis is the final common pathway of progressive kidney diseases including diabetic nephropathy. Here, we report that the endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), the substrate of angiotensin-converting enzyme (ACE), is an orally available peptide drug used to cure kidney fibrosis in diabetic mice. We utilized two mouse models of diabetic nephropathy, streptozotocin- (STZ-) induced type 1 diabetic CD-1 mice and type 2 diabetic nephropathy model db/db mice. Intervention with the ACE inhibitor imidapril, oral AcSDKP, or imidapril + oral AcSDKP combination therapy increased urine AcSDKP levels. AcSDKP levels were significantly higher in the combination group compared to those of the other groups. AcSDKP oral administration, either AcSDKP alone or in addition to imidapril, ameliorated glomerulosclerosis and tubulointerstitial fibrosis. Plasma cystatin C levels were higher in both models, at euthanasia, and were restored by all the treatment groups. The levels of antifibrotic miRs, such as miR-29 or let-7, were suppressed in the kidneys of both models; all treatments, especially the combination of imidapril + oral AcSDKP, restored the antifibrotic miR levels to a normal value or even higher. AcSDKP may be an oral antifibrotic peptide drug that would be relevant to combating fibroproliferative kidney diseases such as diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Activation of the renin-angiotensin system (RAS) in the kidney plays an important role in renal function. The aim of this study was to investigate whether plasma and urinary angiotensinogen levels were associated with renal and cardiovascular prognosis in type 2 diabetic patients. Materials and Methods: We measured plasma and urinary angiotensinogen levels in the observational follow-up cohort of 234 Japanese type 2 diabetic patients (144 with normoalbuminuria, 90 with albuminuria) enrolled between 1998 and 1999 and followed them up until the end of 2008. The associations of these markers with the annual decline in the estimated glomerular filtration rate (eGFR) and incidence of renal and cardiovascular composite endpoints (chronic hemodialysis, myocardial infarction, angina pectoris, stroke and cerebral hemorrhage) were evaluated. Results: At baseline, urinary angiotensinogen levels correlated with urinary albumin-creatinine ratio, urinary β2-microglobulin and inversely with eGFR. In contrast, plasma angiotensinogen levels correlated neither with these renal factors nor with urinary angiotensinogen levels. In the follow-up study (median duration: 9 years), urinary angiotensinogen, but not plasma angiotensinogen, correlated inversely with the annual change in eGFR ( r = −0.51, P < 0.001). When patients were divided into four subgroups according to albuminuria and urinary angiotensinogen levels, patients with albuminuria and high urinary angiotensinogen levels showed a progressive decline of eGFR and a higher incidence of renal and cardiovascular composite endpoints. Conclusions: These results suggest that the higher level of urinary angiotensinogen in type 2 diabetic patients with albuminuria is a high risk factor for worsening renal and cardiovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00172.x, 2011) [ABSTRACT FROM AUTHOR]

Background. The aim of this study was to investigate the annual rate of glomerular filtration rate (GFR) decline and risks for this decline in association with albuminuria progression in type 2 diabetes.Methods. An observational 4-year cohort study was performed on 1002 subjects with preserved GFR (699 normoalbuminuric), and the predictive value of baseline variables on the GFR slope was investigated. GFR decliner and albuminuria progressor were defined as a GFR slope <−4.0%/year and changes in the geometric mean of urinary albumin from baseline to follow-up >150%, respectively.Results. Annual rates of GFR decline (percent per year, median and interquartile range) were −2.58 (−4.70 to −0.48) in normoalbuminuria, −3.49 (−5.93 to −1.11) in microalbuminuria and −6.58 (−10.64 to −3.53) in macroalbuminuria. Subjects cross-classified according to GFR decliner/albuminuria progressor consisted of 51% (−/−), 13% (−/+), 28% (+/−) and 8% (+/+). Common risks for GFR decline and albuminuria progression were retinopathy, neuropathy, hemoglobin A1C (HbA1C) and urinary albumin. Independent significant risks for GFR decline were baseline GFR, systolic blood pressure (SBP), total protein (TP) and hypertension. Proportions with progression to albuminuria were similar between GFR decliners and non-decliners. Multiple linear regression analysis indicated that GFR slope was predicted by baseline variables of urinary albumin, GFR, HbA1C, SBP, plasma TP and retinopathy. These risks appeared variable according to high or low levels of urinary albumin and GFR.Conclusions. Urinary albumin excretion is only one risk factor for albuminuria progression and GFR decline, and other important factors were implicated as important for prevention of end-stage renal disease. [ABSTRACT FROM PUBLISHER]

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPAR&agr;, &dgr; and &ggr;. It has been demonstrated that PPAR&agr; and &ggr; agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPAR&dgr; agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPAR&dgr; agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(2). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNF&agr;. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNF&agr; is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNF&agr;- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-&bgr; activated kinase 1 (TAK1)-NFkB pathway, a common downstream signaling pathway to TNF&agr; receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases. [ABSTRACT FROM AUTHOR]

Background: Interleukin-18 (IL-18), a pro-inflammatory cytokine, is a predictor of cardiovascular and renal disease in diabetic patients. Postprandial hyperglycemia is one of the important factors contributing to an increase in the circulating pro-inflammatory cytokine levels. This study investigated the effect of miglitol, an α-glucosidase inhibitor, on postprandial hyperglycemia and IL-18 levels in diabetic patients with nephropathy. Methods: Fifteen Japanese diabetic patients with persistent proteinuria and preserved renal function were recruited. The patients received 50 mg miglitol thrice daily after the baseline examinations and were followed up for 12 weeks. A meal tolerance test was performed on eight patients at baseline and week 12. The fasting miglitol concentration was measured in seven patients just before the meal tolerance test. Results: There were no changes in the body weight, blood pressure, liver and renal function, and proteinuria from baseline to week 12. However, the levels of glycated hemoglobin and interleukin 18 significantly decreased from baseline to week 12. During the meal tolerance test, plasma glucose was significantly decreased 60 min after treatment with miglitol, whereas the serum concentration of insulin was not changed. Fasting and postprandial levels of IL-18 were significantly decreased from baseline to week 12. Serum miglitol concentrations showed a significantly negative correlation with eGFR ( r = −0.82, p = 0.02). However, the serum miglitol concentrations did not changed during the course of this study. Conclusion: Miglitol improved postprandial hyperglycemia and reduced serum IL-18 levels in patients with stage 3 diabetic nephropathy. Miglitol may therefore prevent atherosclerotic diseases and diabetic micro-vascular complications through decreasing glucose swings and/or the circulating IL-18 level. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS--We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction <50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated. RESULTS--Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI 0.15-0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred. CONCLUSIONS--The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction. Diabetes 56:1727-1730, 2007 [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress-induced apoptosis of renal glomerular cells is an important factor for the development of various kidney diseases. Identification of molecules that modulate this process could lead to the development of new strategies for preventing kidney diseases. In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis. Morphological features of apoptotic cell death (nuclear condensation) and the expression of biochemical proapoptotic markers [cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP)] were assessed in murine mesangial cells (MMCs) exposed to hydrogen peroxide (H2O2). H2O2 increased mesangial cell apoptosis, predominantly through p53 activation by acetylation, which is a posttranscriptional modification for p53 activation. H2O2-induced apoptosis was significantly attenuated in SIRT1-overexpressing MMCs, but enhanced in SIRT1-knockdown MMCs. Although SIRT1 did not affect H2O2-mediated phosphorylation of mitogen-activated protein (MAP) kinase, it interacted with p53 and inhibited H2O2-mediated p53 acetylation but not phosphorylation in MMCs. Our results indicate that SIRT1 can prevent oxidative stress-induced apoptosis through p53 deacetylation in mesangial cells. Upregulation of SIRT1 may provide a new strategy for preventing kidney glomerular diseases. [Copyright &y& Elsevier]

Abstract: N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) was originally reported as a natural inhibitor of the proliferation of stem cells. To elucidate whether Ac-SDKP inhibits the proliferation of human mesangial cells, we examined the effect of Ac-SDKP on fetal calf serum (FCS)- or platelet-derived growth factor (PDGF)-BB-induced DNA synthesis and a cell proliferation. Ac-SDKP inhibited PDGF-BB- or FCS-induced DNA synthesis without cellular toxicity. The protein expression of p53 and p27kip1 was significantly increased by Ac-SDKP. Ac-SDKP also up-regulated the PDGF-BB-stimulated expression of p21cip1 and suppressed PDGF-BB-induced cyclin D1 expression. In p53 knock-out human mesangial cells made with small interference RNA, the protein expression of p21cip1 and p27kip1 was also decreased and the inhibitory effect of Ac-SDKP on mesangial proliferation was completely abolished. Ac-SDKP increased the stability of p53 protein as demonstrated by pulse-chase experiment. These results suggest that p53 is the key mediator of Ac-SDKP-induced inhibition of DNA synthesis through the up-regulation of cell cycle modulators, highlighting a potential effect of Ac-SDKP on various progressive renal diseases. [Copyright &y& Elsevier]

To estimate the frequency of remission/regression of microalbuminuria and to identify factors affecting such outcomes in Japanese patients with type 2 diabetes, we observed 216 patients with type 2 diabetes and microalbuminuria enrolled during an initial 2-year evaluation period for the next 6 years. Remission was defined as shift to normoalbuminuria and regression as a 50% reduction in urinary albumin excretion rate (AER) from one 2-year period to the next. Reduction of urinary AER was frequent, with a 6-year cumulative incidence of 51% (95% CI 42-60) for remission and 54% (45-63) for regression, whereas the frequency of progression to overt proteinuria was 28% (19-37). Microalbuminuria of short duration, the use of renin-angiotensin system-blocking drugs, and lower tertiles for HbA(1c) (<6.95%) and systolic blood pressure (<129 mmHg) were independently associated with remission or regression in the pooled logistic regression analysis. The results indicate that reduction in urinary AER occurs frequently in Japanese patients with type 2 diabetes. Early detection of microalbuminuria and a multifactorial control may result in improved outcomes for diabetic nephropathy and cardiovascular events. [ABSTRACT FROM AUTHOR]

Aims The MARLINA- T2D study (, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/mol), estimated glomerular filtration rate ( eGFR) ≥30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio ( UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin ( n = 182) or placebo ( n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results Baseline mean HbA1c and geometric mean ( gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [ CI], −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was −6.0% (95% CI, −15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the prevention of overt diabetic nephropathy using an angiotensin receptor blocker (ARB) in normotensive and hypertensive Japanese patients with type 2 diabetes. The study found that telmisartan decreased the transition rate to overt nephropathy after adjustment for changes in systolic blood pressure (SBP). It also revealed that patients with type 2 diabetes and microalbuminuria receiving telmisartan achieved better renoprotection.

The biguanide metformin has been used for treating insulin resistance and type 2 diabetes. Moreover, the UK prospective diabetes study (UKPDS) showed that metformin could reduce macrovascular morbility and mortality, suggesting anti-atherogenic and anti-inflammatory effects of metformin. However, it is not known whether metformin itself is able to reduce the risk for diabetic kidney disease like other insulin sensitizing agent, thiazolidinediones. The aim of present study is to determine the direct effect of metformin on the expression of the important molecules implicated in the progression of diabetic nephropathy in kidney cells in vitro. We used human renal proximal tubular epithelial cells (HRPTEC) because tubulo-interstitial injury was shown to play an important role in the progression of diabetic nephropathy. First, we identified the proteins secreted from HRPTEC exposed to 2.5 ng/ml TGF-β[sub 1], an important cytokine for the progression of diabetic nephropathy, using LC-MS/MS-based proteomic technique. Several proteins were identified to be upregulated by TGF-β[sub 1], one of which was plasminogen activator inhibitor-1 (PAI-1). In the Western blot analysis, TGF-β[sub 1]-induced PAI-1 protein secretion was significantly suppressed by the pretreatment of metformin in a dose-dependent fashion (0.1mM-10mM). We next examined the effect of metformin on the expression of genes induced by TGF-β[sub 1] by quantitative real-time RT-PCR. Metformin inhibited TGF-β[sub 1]-induced monocyte chemoattractant protein-1 (MCP-1), PAI-1, fibronectin, and collagen-1 mRNA expression. Moreover, metformin was also able to inhibit angiotensin II-induced MCP-1, collagen-1 mRNA expression. An activator of AMP-activated protein kinase (AMPK), which was known to be activated by metformin, 5-amino-4-imidazole carboxamide riboside (AICAR) also partially suppressed. MCP-1 mRNA expression. In conclusion, our results indicate that metformin not only inhibits TGF-β[sub 1]induced PAI-1 secretion, but also suppresses the expression of multiple genes linked to the progressive pathways in the diabetic nephropathy partly through the activation of AMPK. This action of metformin could be applied to prevent the progression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic nephropathy in type 2 diabetes is a leading cause of end-stage renal disease worldwide. Its early clinical sign is microalbuminuria, which is not only a predictor for progression of nephropathy but also an independent risk factor for cardiovascular disease. A few decades ago, diabetic nephropathy was believed to be progressive and irreversible. Thus, the main therapeutic objective for type 2 diabetic patients with microalbuminuria was to prevent progression to overt proteinuria. However, there is now growing evidence regarding remission/regression of diabetic nephropathy. In recent clinical trials using the renin-angiotensin system blockade drugs, a reduction in microalbuminuria by the use of these drugs has been noted. We also reported that a reduction in microalbuminuria was more frequent than progression to overt proteinuria and that multifactorial control approach was important to the reduction of microalbuminuria. These results for type 2 diabetes are similar to those previously reported for type 1 diabetes. Furthermore, our recent study showed that the 8-year cumulative incidence rate of renal and cardiovascular events was significantly lower in patients with remission than in those without it. The annual decline rate of estimated glomerular filtration rate in patients with remission was also significantly slower. These studies provide clinical evidence implying that the reduction of microalbuminuria in type 2 diabetic patients occurs frequently and brings about renal and cardiovascular risk reduction. Reducing microalbuminuria is therefore considered to be an important therapeutic objective and may be a biomeasure of therapeutic success in type 2 diabetic patients. [Copyright &y& Elsevier]

As renal lipotoxicity can lead to chronic kidney disease (CKD), we examined the role of peroxisome proliferator-activated receptor (PPAR)-α, a positive regulator of renal lipolysis. Feeding mice a high-fat diet induced glomerular injury, and treating them with fenofibrate, a PPARα agonist, increased the expression of lipolytic enzymes and reduced lipid accumulation and oxidative stress in glomeruli, while inhibiting the development of albuminuria and glomerular fibrosis. In mice given an overload of free fatty acid-bound albumin to induce tubulointerstitial injury, fenofibrate attenuated the development of oxidative stress, macrophage infiltration, and fibrosis, and enhanced lipolysis in the renal interstitium. Fenofibrate inhibited palmitate-induced expression of profibrotic plasminogen activator inhibitor-1 (PAI-1) in cultured mesangial cells, and the expression of both monocyte chemoattractant protein-1 and PAI-1 in proximal tubular cells along with the overexpression of lipolytic enzymes. Thus, fenofibrate can attenuate lipotoxicity-induced glomerular and tubulointerstitial injuries, with enhancement of renal lipolysis. Whether amelioration of renal lipotoxicity by PPARα agonists will turn out to be a useful strategy against CKD will require direct testing. [ABSTRACT FROM AUTHOR]

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage. [ABSTRACT FROM AUTHOR]