Aldosterone induces myocardial fibrosis and vascular inflammation via proinflammatory and profibrotic cytokines. The effect of spironolactone on renal inflammation and renal function was investigated in type 2 diabetic rats. For define the molecular mechanism of spironolactone, the effect of spironolactone on the synthesis of monocyte chemotactic peptide-1 (MCP-1) and its upstream transcription factor, NF-B, was evaluated in cultured mesangial cells and proximal tubular cells. There were no changes in blood glucose concentration or BP after spironolactone treatment. Spironolactone treatment significantly reduced urinary albumin excretion and ameliorated glomerulosclerosis. Urinary levels of MCP-1 were significantly increased concurrently with renal expression of MCP-1, macrophage migration inhibitory factor, and macrophage infiltration. Spironolactone treatment significantly inhibited urinary excretion of MCP-1 as well as renal MCP-1 and migration inhibitory factor expression and macrophage infiltration. In addition, aldosterone induced upregulation of MCP-1 expression and NF-B transcriptional activity in cultured cells, and spironolactone reduced both NF-B activation and MCP-1 synthesis. Furthermore, NF-B inhibition abolished aldosterone-induced MCP-1 production. Overall, these findings suggest that aldosteroneinduced NF-B activation leads to activation of proinflammatory cytokines, ultimately leading to renal injury in this model. These data suggest that mineralocorticoid blockade may be a potential therapeutic target in diabetic nephropathy.

The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.

BackgroundSoluble amyloid-β (Aβ) oligomers are the major toxic substances associated with the pathology of Alzheimer’s disease (AD). The ability to measure Aβ oligomer levels in the blood would provide simple and minimally invasive tools for AD diagnostics. In the present study, the recently developed Multimer Detection System (MDS) for AD, a new enzyme-linked immunosorbent assay for measuring Aβ oligomers selectively, was used to detect Aβ oligomers in the plasma of patients with AD and healthy control individuals.MethodsTwenty-four patients with AD and 37 cognitively normal control individuals underwent extensive clinical evaluations as follows: blood sampling; detailed neuropsychological tests; brain magnetic resonance imaging; cerebrospinal fluid (CSF) measurement of Aβ42, phosphorylated tau protein (pTau), and total tau protein (tTau); and 11C-Pittsburgh compound B (PIB) positron emission tomography. Pearson’s correlation analyses between the estimations of Aβ oligomer levels by MDS and other conventional AD biomarkers (CSF Aβ42, pTau, and tTau, as well as PIB standardized uptake value ratio [PIB SUVR]) were conducted. ROC analyses were used to compare the diagnostic performance of each biomarker.ResultsThe plasma levels of Aβ oligomers by MDS were higher in patients with AD than in normal control individuals, and they correlated well with conventional AD biomarkers (levels of Aβ oligomers by MDS vs. CSF Aβ42, r = −0.443; PIB SUVR, r = 0.430; CSF pTau, r = 0.530; CSF tTau, r = 0.604). The sensitivity and specificity of detecting plasma Aβ oligomers by MDS for differentiating AD from the normal controls were 78.3% and 86.5%, respectively. The AUC for plasma Aβ oligomers by MDS was 0.844, which was not significantly different from the AUC of other biomarkers (p = 0.250).ConclusionsPlasma levels of Aβ oligomers could be assessed using MDS, which might be a simple, noninvasive, and accessible assay for evaluating brain amyloid deposition related to AD pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0324-0) contains supplementary material, which is available to authorized users.

Despite the emerging importance of fibroblast growth factor 21 (FGF21) as a metabolic hormone regulating energy balance, its direct effects on renal function remain unexplored. FGF21 was injected ip daily for 12 weeks into db/db mice. Compared with control vehicle injection, FGF21 treatment significantly improved lipid profiles and insulin resistance and resulted in significantly higher serum adiponectin levels. In contrast, serum insulin and 8-isoprostane levels were significantly decreased. Interestingly, FGF21 and its receptor components in the kidneys were found to be significantly up-regulated in db/db mice, which suggests an FGF21-resistant state. FGF21 treatment significantly down-regulated FGF21 receptor components and activated ERK phosphorylation. FGF21 administration also markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic molecule synthesis. Furthermore, FGF21 improved renal lipid metabolism and oxidative stress injury. In cultured renal cells, FGF21 was mainly expressed in mesangial cells, and knockdown of FGF21 expression by stealth small interfering RNA further aggravated high-glucose-induced profibrotic cytokine synthesis in mesangial cells. Our results suggest that FGF21 improves insulin resistance and protects against renal injury through both improvement of systemic metabolic alterations and antifibrotic effects in type 2 diabetic nephropathy. Targeting FGF21 could therefore provide a potential candidate approach for a therapeutic strategy in type 2 diabetic nephropathy.

The NF-κB pathway plays an important role in chronic inflammatory and autoimmune diseases. Recently, NF-κB has also been suggested as an important mechanism linking obesity, inflammation, and metabolic disorders. However, there is no current evidence regarding the mechanism of action of NF-κB inhibition in insulin resistance and diabetic nephropathy in type 2 diabetic animal models. We investigated the effects of the NF-κB inhibitor celastrol in db/db mice. The treatment with celastrol for 2 months significantly lowered fasting plasma glucose (FPG), HbA1C and homeostasis model assessment index (HOMA-IR) levels. Celastrol also exhibited significant decreases in body weight, kidney/body weight and adiposity. Celastrol reduced insulin resistance and lipid abnormalities and led to higher plasma adiponectin levels. Celastrol treatment also significantly mitigated lipid accumulation and oxidative stress in organs including the kidney, liver and adipose tissue. The treated group also exhibited significantly lower creatinine levels and urinary albumin excretion was markedly reduced. Celastrol treatment significantly lowered mesangial expansion and suppressed type IV collagen, PAI-1 and TGFβ1 expressions in renal tissues. Celastrol also improved abnormal lipid metabolism, oxidative stress and proinflammatory cytokine activity in the kidney. In cultured podocytes, celastrol treatment abolished saturated fatty acid-induced proinflammatory cytokine synthesis. Taken together, celastrol treatment not only improved insulin resistance, glycemic control and oxidative stress, but also improved renal functional and structural changes through both metabolic and anti-inflammatory effects in the kidney. These results suggest that targeted therapy for NF-κB may be a useful new therapeutic approach for the management of type II diabetes and diabetic nephropathy.