Association of xanthine oxidoreductase inhibitor use with insulin secretory capacity in patients with type 2 diabetes.

AIM/INTRODUCTION: Xanthine oxidoreductase (XOR) inhibitor treatment, which reduces reactive oxygen species (ROS) production and increases adenosine triphosphate (ATP) synthesis, has been reported to improve glycemic control. The possible protective effects of XOR inhibitor treatment on insulin secretory capacity were investigated in patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective cross-sectional study included 428 patients with type 2 diabetes. Insulin secretory capacity was assessed based on fasting serum C-peptide concentration (CPR) and C-peptide index (CPI) in all subjects, while insulin resistance in non-insulin users (n = 312) was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. RESULTS: Median values for CPR and CPI in all subjects were 2.4 ng/mL and 1.5, respectively, while that for HOMA-IR in non-insulin users was 3.2. The XOR inhibitor users (n = 72) had significantly (P < 0.001) higher CPR and CPI levels than non-users (n = 356). Multivariable regression analyses showed XOR inhibitor use was positively associated with CPR (ß = 0.153, P = 0.001) and CPI (ß = 0.144, P = 0.001). Similar results were observed in propensity score analyses. In subgroup analyses of patients with a preserved estimated glomerular filtration rate (≥60 mL/min/1.73 m2) and non-insulin users, these associations remained significant. Furthermore, the associations were significant in patients with lower (≤6.0 mg/dL) but not with higher (>6.0 mg/dL) uric acid levels (P for interaction <0.05). On the other hand, XOR inhibitor use showed no significant association with HOMA-IR. CONCLUSIONS: The results of XOR inhibitor treatment, especially a sufficient reduction in serum uric acid level, may provide protective effects on insulin secretory capacity in patients with type 2 diabetes.

Differential associations of fetuin-A and calcification propensity with cardiovascular events and subsequent mortality in patients undergoing hemodialysis.

Background: Fetuin-A inhibits precipitation of calcium-phosphate crystals by forming calciprotein particles (CPP). A novel T50 test, which measures transformation time from primary to secondary CPP, is an index for calcification propensity. Both lower fetuin-A and shorter T50 levels were associated with cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). Extremely high risk for CVD death in advanced CKD patients consists of high-incidental CVD event and high mortality after CVD event. To date, it is unclear whether fetuin-A and/or T50 can equally predict each CVD outcome. Methods: This prospective cohort study examined patients undergoing maintenance hemodialysis. The exposures were fetuin-A and T50. The outcomes of interests were new CVD events and subsequent deaths. The patients were categorized into tertiles of fetuin-A or T50 (T1 to T3). Results: We identified 190 new CVD events during the 5-year follow-up of the 513 patients and 59 deaths subsequent to the CVD events during 2.5-year follow-up. A lower fetuin-A but not T50 was significantly associated with new CVD events [subdistribution hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.15-2.61, P = .009 for T1 vs T3]. In contrast, a shorter T50 but not fetuin-A was a significant predictor of deaths after CVD events (HR 3.31, 95% CI 1.42-7.74, P = .006 for T1 + T2 vs T3). A lower fetuin-A was predictive of new CVD events, whereas a shorter T50 was more preferentially associated with subsequent death. Conclusion: These results indicate that fetuin-A and T50 are involved in cardiovascular risk in different manners.

Serum Fibroblast Growth Factor 23 Levels are Associated with Vascular Smooth Muscle Dysfunction in Type 2 Diabetes.

AIM: Increased level of serum fibroblast growth factor 23 (FGF23) is a hallmark of abnormal phosphate metabolism in patients with chronic kidney disease (CKD) and is recently shown to be associated with the risk of cardiovascular disease even in those without CKD. This study investigated the association between serum FGF23 levels and vascular function in patients with type 2 diabetes. METHODS: This was a cross-sectional study involving 283 Japanese patients with type 2 diabetes. Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) of the brachial artery were measured via ultrasonography to evaluate vascular endothelial and smooth muscle functions, respectively. Serum intact FGF23 levels were determined via a sandwich enzyme-linked immunosorbent assay. RESULTS: The median values of FMD, NMD, and serum FGF23 were 6.0%, 14.0%, and 27.3 pg/mL, respectively. The serum FGF23 levels were inversely associated with NMD but not with FMD, and the association was independent of atherosclerotic risk factors, estimated glomerular filtration rate (eGFR), and serum phosphate levels. Furthermore, the relationship between serum FGF23 levels and NMD was modified by kidney function, which was pronounced in subjects with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2). CONCLUSION: Serum FGF23 levels are independently and inversely associated with NMD in patients with type 2 diabetes, particularly in those with normal kidney function. Our results indicate that FGF23 is involved in vascular smooth muscle dysfunction and that increased serum levels of FGF23 may serve as a novel biomarker for vascular smooth muscle dysfunction in patients with type 2 diabetes.

Factors associated with atrial fibrillation in Japanese patients with type 2 diabetes mellitus: a cross-sectional study.

Aims: Atrial fibrillation (AF) increases cardiovascular complications and mortality in patients with diabetes. Diabetes is a risk factor for AF; however, risk factors for AF among patients with type 2 diabetes (T2D) remain unknown, especially among Asian people. We clarified the prevalence of AF, regardless of type (i.e., paroxysmal, persistent, or permanent) in Japanese patients with T2D and clarified factors associated with AF. Methods: This cross-sectional study was conducted at Fujiidera Municipal Hospital (Osaka, Japan). Patients with T2D (n = 899: 518 men and 381 women with a mean age ± SD of 69.0 ± 12.1 years) were included. Their electrocardiographs were checked during routine examinations between January 2017 and January 2018. A diagnosis of AF was determined from single time-point standard 12-lead electrocardiographic findings. We analyzed clinical parameters (e.g., age, sex, diabetes duration, glycated hemoglobin, body mass index, estimated glomerular filtration rate, albuminuria or proteinuria, use of biguanide, and presence of hypertension) between patients with and without AF. Results: The prevalence of AF among patients with T2D was 5.9%; it became higher as age increased and tended to be higher in men than in women. The prevalence became higher as albuminuria or proteinuria progressed and as the eGFR decreased. Multiple logistic regression analyses revealed that older age, male sex, and reduced eGFR were independently and significantly associated with the coexistence of AF. However, multiple logistic regression analysis revealed no significant relationships between AF and the presence of albuminuria or proteinuria. Conclusions: Older age, male sex, and reduced eGFR were associated with AF in Japanese patients with T2D. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00563-w.

New-onset Type 1 Diabetes after COVID-19 mRNA Vaccination.

During the ongoing coronavirus disease 2019 (COVID-19) pandemic, it is critical to ensure the safety of COVID-19 vaccines. We herein report a 51-year-old Japanese woman who developed acute-onset type 1 diabetes with diabetic ketoacidosis six weeks after receiving the first dose of a COVID-19 messenger ribonucleic acid (mRNA) vaccine. Laboratory tests indicated exhaustion of endogenous insulin secretion, a positive result for insulin autoantibody, and latent thyroid autoimmunity. Human leukocyte antigen typing was homozygous for DRB1*09:01-DQB1*03:03 haplotypes. This case suggests that COVID-19 vaccination can induce type 1 diabetes in some individuals with a genetic predisposition.

New-onset fulminant type 1 diabetes after severe acute respiratory syndrome coronavirus 2 vaccination: A case report.

Fulminant type 1 diabetes is characterized by a rapid progression of insulin deficiency triggered by viral infection. Here, we report a case of a 45-year-old Japanese woman with fulminant type 1 diabetes that developed 8 days after receiving messenger ribonucleic acid vaccine against severe acute respiratory syndrome coronavirus 2. She had been healthy and had no symptoms suggestive of viral infection before the vaccination. Laboratory tests showed exhaustion of insulin secretion and negative results for islet autoantibodies. Human leukocyte antigen genotype analysis showed the DRB1*04:05 and DQB1*04:01 alleles. This is the first case report of new-onset fulminant type 1 diabetes after severe acute respiratory syndrome coronavirus 2 vaccination, and suggests that a severe acute respiratory syndrome coronavirus 2 vaccine might trigger the onset of fulminant type 1 diabetes in susceptible individuals. However, a causal relationship remains to be identified, and further studies are required to determine the incidence of such cases.

Nutritional Disorder Evaluated by the Geriatric Nutritional Risk Index Predicts Death After Hospitalization for Infection in Patients Undergoing Maintenance Hemodialysis.

OBJECTIVE: Infection is related to a higher rate of hospitalization and subsequent death in patients undergoing hemodialysis. Limited data are available about factors associated with death after hospitalization for infection. Nutritional disorder also known as protein energy wasting is profoundly associated with poor consequences. The Geriatric Nutritional Risk Index (GNRI) is a simple but useful nutritional screening tool to predict mortality. We examined whether the GNRI could predict hospitalization for infection and subsequent death. DESIGN AND METHODS: This was a prospective cohort study on patients undergoing hemodialysis. The predictor was the GNRI. The patients were divided into tertiles of the GNRI (T1 to T3), with the highest tertile of T3 as the referent. The outcomes of interest were all-cause mortality, hospitalization for infection, and subsequent death. RESULTS: Of 518 patients, 107 patients died (median follow-up period: 5.0 years; interquartile range: 3.6-5.0) and 169 patients experienced new hospitalization for infection (median follow-up period: 4.5 years; interquartile range: 3.4-5.0) during the follow-up period from December 2004 to December 2009. A lower GNRI was a significant predictor for all-cause mortality in multivariable Cox models (hazard ratio [HR]: 2.9, 95% confidential interval [CI]: 1.5-5.5, P < .001 for T1 vs. T3). However, the GNRI was not associated with hospitalization for infection in multivariable Fine-Gray models with death as a competing risk (subdistributional HR: 1.5, 95% CI: 1.0-2.3, P = .056 for T1 vs. T3). After hospitalization for infection, 38 patients died during the subsequent 2.5-year follow-up period. The GNRI was a significant predictor of death after hospitalization for infection in multivariable Cox models (HR: 2.7, 95% CI: 1.3-5.6, P = .006 for T1 vs. T2+T3). CONCLUSIONS: A lower GNRI predicted a higher risk of all-cause mortality but not hospitalization for infection. However, a lower GNRI was significantly associated with a higher risk of mortality after hospitalization for infection. These findings suggest that long-term mortality after hospitalization for infection was predicted by nutritional disorder evaluated by the GNRI.

Role of adiponectin in the relationship between visceral adiposity and fibroblast growth factor 23 in non-diabetic men with normal kidney function.

Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate metabolism. Circulating FGF23 levels are associated with obesity, metabolic syndrome, and cardiovascular disease in the general population, but the underlying mechanism remains unclear. Therefore, we aimed to determine the associations between serum FGF23 levels and visceral adiposity as well as serum adiponectin levels in 189 adults without diabetes and with normal kidney function who were selected from the MedCity21 health examination registry. The exclusion criteria included diabetes mellitus or impaired kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Levels of serum FGF23 and total adiponectin, and visceral fat area (VFA) on computed tomography images were measured. Serum FGF23 levels were higher and VFA was greater, whereas serum adiponectin levels were lower in men than in women. Serum FGF23 levels positively correlated with VFA in men; they remained marginally significant after adjusting for age, eGFR, and serum levels of calcium, phosphate, intact parathyroid hormone, and 1,25-dihydroxyvitamin D. Importantly, when serum adiponectin levels were included as a covariate, serum adiponectin levels comprised an independent determinant of serum FGF23 levels in men, whereas VFA did not. In conclusion, lower serum adiponectin, rather than a greater VFA, was associated with higher serum FGF23 levels in non-diabetic men with normal kidney function. These findings suggest that adiponectin plays a role in the relationship between visceral adiposity and FGF23 in men.

Effects of fetuin-A-containing calciprotein particles on posttranslational modifications of fetuin-A in HepG2 cells.

Fetuin-A is an inhibitor of ectopic calcification that is expressed mainly in hepatocytes and is secreted into the circulation after posttranslational processing, including glycosylation and phosphorylation. The molecular weight (MW) of fully modified fetuin-A (FM-fetuin-A) is approximately 60 kDa in an immunoblot, which is much higher than the estimated MW by amino acid sequence. Under conditions of calcification stress such as advanced stage chronic kidney disease, fetuin-A prevents calcification by forming colloidal complexes, which are referred to as calciprotein particles (CPP). Since the significance of CPP in this process is unclear, we investigated the effect of synthetic secondary CPP on the level of FM-fetuin-A in HepG2 cells. Secondary CPP increased the level of FM-fetuin-A in dose- and time-dependent manners, but did not affect expression of mRNA for fetuin-A. Treatment with O- and/or N-glycosidase caused a shift of the 60 kDa band of FM-fetuin-A to a lower MW. Preincubation with brefeldin A, an inhibitor of transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi apparatus, completely blocked the secondary CPP-induced increase in FM-fetuin-A. Treatment with BAPTA-AM, an intracellular calcium chelating agent, also inhibited the CPP-induced increase in the FM-fetuin-A level. Secondary CPP accelerate posttranslational processing of fetuin-A in HepG2 cells.

Low Free Triiodothyronine Level as a Predictor of Cardiovascular Events and All-Cause Mortality in Patients Undergoing Hemodialysis: The DREAM Cohort.

AIM: Low T3 syndrome is characterized by low serum triiodothyronine (T3) levels without elevation of thyroid-stimulating hormone (TSH) in patients without apparent thyroid disease, which is known to be associated with worse clinical outcomes in various populations including those with kidney failure. In this study, we examined whether low free T3 (FT3) levels are independent predictor of cardiovascular disease (CVD) events in patients undergoing hemodialysis. METHODS: This was a prospective cohort study of patients with chronic kidney disease undergoing hemodialysis. From the total of 518 patients, we excluded patients with treated or untreated hyperthyroidism or hypothyroidism and those treated with corticosteroids. RESULTS: We analyzed data from 438 eligible patients. During the 5-year follow-up, 154 new CVD events and 86 all-cause deaths were recorded. Kaplan-Meier analysis showed that lower FT3 levels were associated with higher risks for new cardiovascular events and all-cause death. This inverse association of FT3 and new CVD events remained significant after adjustment for age, sex, duration of hemodialysis, diabetic kidney disease, hypertension, dyslipidemia, and smoking; however, it was no longer significant after further adjustment for prior CVD or N-terminal fragment of probrain natriuretic peptide (NT-proBNP). FT3 did not show an independent association with all-cause mortality. CONCLUSIONS: Our results indicate that low FT3 status is not an independent predictor of new CVD events and that the following factors are closely associated: prior CVD, low FT3 and high NT-proBNP levels at present, and future risk of new CVD events in hemodialysis patients.

Albuminuria rather than glomerular filtration rate is associated with vascular endothelial function in patients with type 2 diabetes.

AIMS: Albuminuria and reduced glomerular filtration rate (GFR) are manifestations of diabetic kidney disease and are both shown to be associated with cardiovascular outcomes. However, the differential association of albuminuria and reduced GFR with endothelial dysfunction, an early feature of atherosclerotic vascular damage, remains unclear. In this study, we investigated the association between albuminuria or estimated GFR (eGFR) and flow-mediated dilatation (FMD), a marker of endothelial function, in patients with type 2 diabetes. METHODS: This study included 633 patients with type 2 diabetes. The FMD of the brachial artery was measured by ultrasonography. Albuminuria was evaluated by urinary albumin-to-creatinine ratio (ACR). RESULTS: The mean FMD and eGFR, and the median value of ACR were 6.7%, 66.5 mL/min/1.73m2 and 12.5 mg/g creatinine, respectively. Impaired FMD was found in patients with advanced stages of chronic kidney disease based on both GFR and albuminuria categories. Multivariate analysis after adjusting for potential confounders revealed that ACR, but not eGFR, was significantly and inversely associated with FMD. CONCLUSIONS: Albuminuria is associated with FMD, independently of traditional cardiovascular risk factors in patients with type 2 diabetes. This study suggests a close relationship between albuminuria, rather than reduced GFR, and endothelial dysfunction in type 2 diabetes.

Inter-Arm Blood Pressure Difference in Diabetes Mellitus and Its Preferential Association with Peripheral Artery Disease.

AIM: Inter-arm blood pressure difference (IAD) is known to be associated with a composite of cardiovascular disease (CVD) and with CVD risk factors. However, only limited information is available regarding the contribution of diabetes mellitus to IAD and the association of IAD with individual CVDs, such as coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). METHODS: We addressed these issues in this cross-sectional study of 2580 participants who had simultaneous blood pressure measurements in both arms using an automated device. RESULTS: Compared with 1,264 nondiabetic subjects, 1316 patients with diabetes mellitus had a greater IAD (P=0.01) and a higher prevalence of IAD of ≥ 10 mmHg (8.4% vs. 5.4%, P=0.002). However, such difference was not significant after the adjustment for potential confounders. Among CAD, stroke, and PAD, only PAD was significantly associated with IAD in a model adjusted for the CVD risk factors. Age was found to modify the association between IAD and PAD, with the association being more prominent in the younger subgroup. CONCLUSION: Thus, diabetes mellitus itself was not an independent factor associated with IAD. A larger IAD was preferentially associated with the presence of PAD, and this association was modified by age.

Secretory Leukocyte Protease Inhibitor (SLPI)-A Novel Predictive Biomarker of Acute Kidney Injury after Cardiac Surgery: A Prospective Observational Study.

Acute kidney injury (AKI) is one of the most frequent complications after cardiac surgery and is associated with poor outcomes. Biomarkers of AKI are crucial for the early diagnosis of this condition. Secretory leukocyte protease inhibitor (SLPI) is an alarm anti-protease that has been implicated in the pathogenesis of AKI but has not yet been studied as a diagnostic biomarker of AKI. Using two independent cohorts (development cohort (DC), n = 60; validation cohort (VC), n = 148), we investigated the performance of SLPI as a diagnostic marker of AKI after cardiac surgery. Serum and urinary levels of SLPI were quantified by ELISA. SLPI was significantly elevated in AKI patients compared with non-AKI patients (6 h, DC: 102.1 vs. 64.9 ng/mL, p < 0.001). The area under the receiver operating characteristic curve of serum SLPI 6 h after surgery was 0.87 ((0.76-0.97); DC). The addition of SLPI to standard clinical predictors significantly improved the predictive accuracy of AKI (24 h, VC: odds ratio (OR) = 3.91 (1.44-12.13)). In a subgroup, the increase in serum SLPI was evident before AKI was diagnosed on the basis of serum creatinine or urine output (24 h, VC: OR = 4.89 (1.54-19.92)). In this study, SLPI was identified as a novel candidate biomarker for the early diagnosis of AKI after cardiac surgery.

Oncostatin M induces C2C12 myotube atrophy by modulating muscle differentiation and degradation.

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays a role in various disorders such as cancer and inflammatory diseases, which are often accompanied by skeletal muscle atrophy, or sarcopenia. However, the role of OSM in the regulation of skeletal muscle mass remains to be identified. In this study, we investigated the effect of OSM on C2C12 myotube formation in vitro. C2C12 myoblasts were induced to differentiate into myotubes for 3 days and then treated with OSM for 24 or 48 h. The diameter of differentiated C2C12 myotubes were reduced by 18.7% and 23.3% compared to control cells after treatment with OSM for 24 and 48 h, respectively. The expression levels of MyoD and myogenin were decreased, while those of atrogin-1, CCAAT/enhancer binding protein δ, and OSM receptor were increased in C2C12 myotubes treated with OSM for 24 h compared to control cells. Furthermore, the inhibitory effect of OSM on myotube formation was significantly attenuated by pretreatment with an inhibitor of signal transducer and activator of transcription (STAT) 3 or by knockdown of Stat3. Finally, the OSM-induced changes in the expression levels of MyoD, myogenin, and atrogin-1 were reversed by pretreatment with an inhibitor of STAT3 or by Stat3 knockdown in C2C12 myotubes. In conclusion, OSM induces C2C12 myotube atrophy by inhibiting myogenic differentiation and activating muscle degradation in a STAT3-dependent manner.

Association of Albuminuria With Intraglomerular Hydrostatic Pressure and Insulin Resistance in Subjects With Impaired Fasting Glucose and/or Impaired Glucose Tolerance.

OBJECTIVE: Little is known about the relationships between insulin resistance, intrarenal hemodynamics, and urinary albumin excretion (UAE) in humans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). The aim of the current study was to examine intrarenal hemodynamic abnormalities, insulin resistance, and UAE in subjects with IFG or IGT. We hypothesized that intrarenal hemodynamic abnormalities would be associated with insulin resistance. RESEARCH DESIGN AND METHODS: Fifty-four kidney donors underwent 75-g oral glucose tolerance and inulin and para-aminohippuric acid clearance testing. Insulin sensitivity index (ISI) was evaluated by the Matsuda index. Intrarenal hemodynamic parameters were calculated by the Gomez formulae. RESULTS: Of the 54 subjects, 33 exhibited IFG or IGT and 31 exhibited normal glucose tolerance (NGT). Glomerular hydrostatic pressure (Pglo) and UAE were significantly higher in the IFG or IGT subjects with obesity (P = 0.015 and 0.0001, respectively). Log ISI correlated significantly and negatively with Pglo (r = -0.351, P = 0.009) in all subjects. In multiple regression analyses among all subjects, log ISI was associated significantly and independently with Pglo (ß = -0.316, P = 0.015), after adjustment for age, sex, and systolic blood pressure. Further, BMI (ß = 0.517, P = 0.0004), Pglo (ß = 0.420, P = 0.004), and log ISI (ß = -0.366, P = 0.008) were each associated significantly and independently with UAE after adjustment. CONCLUSIONS: We demonstrated that increased insulin resistance is associated with increased Pglo and UAE in IFG or IGT subjects. These hemodynamic burdens and insulin resistance may cause injury to the glomeruli even in subjects with IFG or IGT.

The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif-/- mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.

MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms.

Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions that is produced by several organs and cell types. Depending on the target cell and the inflammatory context, MIF can engage its two component receptor complex CD74 and CD44 and the chemokine receptors CXCR2/4. MIF is constitutively expressed in renal proximal tubular cells, stored in intracellular preformed pools, and released at a low rate. Recently, a second MIF-like protein (i.e., MIF-2/D-DT) has been characterized in mammals. Our study was aimed at examining the role of MIF-2/D-DT, which mediates tissue protection in the heart, in tubular cell regeneration from ischemia-reperfusion injury. We found that Mif-/-, Mif-2-/-, and Cd74-/- mice had significantly worse tubular injury compared with wild-type (WT) control mice and that treatment with MIF-2/D-DT significantly improved recovery of injured epithelial cells. RNAseq analysis of kidney tissue from the ischemia-reperfusion injury model revealed that MIF-2/D-DT treatment stimulates secretory leukocyte proteinase inhibitor (SLPI) and cyclin D1 expression. MIF-2/D-DT additionally activates of eukaryotic initiation factor (eIF) 2α and activating transcription factor (ATF) 4, two transcription factors involved in the integrated stress response (ISR), which is a cellular stress response activated by hypoxia, nutrient deprivation, and oxygen radicals. MIF-2/D-DT also inhibited apoptosis and induced autophagy in hypoxia-treated mouse proximal tubular (MPT) cells. These results indicate that MIF-2/D-DT is an important factor in tubular cell regeneration and may be of therapeutic utility as a regenerative agent in the clinical setting of ischemic acute kidney injury.

Relationship between serum uric acid levels and intrarenal hemodynamic parameters.

BACKGROUND/AIMS: Hyperuricemia has been reported to affect renal hemodynamics in rat models. We evaluate the relationship between serum uric acid and intrarenal hemodynamic parameters in humans, utilizing the plasma clearance of para-aminohippurate (CPAH ) and inulin (Cin). METHODS: Renal and glomerular hemodynamics were assessed by simultaneous measurement of CPAH and Cin in 58 subjects. Of these, 19 subjects were planned to provide a kidney for transplantation; 26 had diabetes without proteinuria; and 13 had mild proteinuria. Renal and glomerular hemodynamics were calculated using Gomez`s formulae. RESULTS: Cin was more than 60 ml/min/1.73m(2) in all subjects. Serum uric acid levels correlated significantly with vascular resistance at the afferent arteriole (Ra) (r = 0.354, p = 0.006) but not with that of the efferent arteriole (Re). Serum uric acid levels (ß = 0.581, p = <0.001) were significantly and independently associated with Ra after adjustment for several confounders (R(2) = 0.518, p = <0.001). CONCLUSIONS: These findings suggest, for the first time in humans, that higher serum uric acid levels are associated significantly with Ra in subjects with Cin > 60 ml/min/1.73m(2). The increase in Ra in subjects with higher uric acid levels may be related to dysfunction of glomerular perfusion.

Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells.

BACKGROUND: Fetuin-A is a liver-derived circulating protein that has potent calcification-inhibitory activity. Uraemic patients exhibit decreased serum fetuin-A levels, increased vascular calcification and elevated cardiovascular mortality. Because the mechanisms for fetuin-A deficiency are unknown, we hypothesized that some uraemic toxins suppressed hepatic fetuin-A production, which resulted in accelerated vascular calcification and poor outcome. Among these potential candidates, indoxyl sulfate (IS) has highly toxic properties. METHODS: We examined the direct effects of IS on hepatic fetuin-A expression using the human hepatoma HepG2 cell line. RESULTS: IS, but not p-cresyl sulfate, suppressed the mRNA and protein expression of fetuin-A in a dose- and time-dependent manner. As reported previously, IS stimulated p38 MAPK phosphorylation and reactive oxygen species (ROS) production, although the knockdown of p38 and inhibition of ROS generation had no effect on IS-induced fetuin-A suppression. Then, because IS is a potent endogenous ligand of the aryl hydrocarbon receptor (AhR), we assessed whether IS suppresses fetuin-A production via AhR. The knockdown of AhR prevented IS-induced fetuin-A suppression. However, some attention should be paid to no effect of IS on fetuin-A expression in mouse and human primary cultured hepatocytes. CONCLUSIONS: These findings suggest that IS could suppress hepatic fetuin-A expression by activating AhR, suggesting a relationship between uraemia and fetuin-A deficiency.

Significant association between glycemic status and increased estimated postglomerular resistance in nondiabetic subjects - study of inulin and para-aminohippuric acid clearance in humans.

We investigated whether glomerular hemodynamic parameters in nondiabetic subjects, including healthy subjects, are associated with glycemic status indices, by simultaneous measurement of inulin (Cin) and para-aminohippuric acid (CPHA) clearance. Twenty-six subjects (age 49.5 ± 13.3 years; 13 men and 13 women; 14 healthy subjects and 12 subjects with mild proteinuria) were enrolled. Cin and CPAH were measured simultaneously. All 26 subjects were nondiabetics. Estimated preglomerular resistance, estimated postglomerular resistance, and estimated glomerular hydrostatic pressure (Pglo) were calculated according to Gomez' formula. Pglo correlated significantly and positively with hemoglobin A1c (HbA1c) in both healthy subjects (r = 0.532, P = 0.0498) and subjects with mild proteinuria (r = 0.681, P = 0.015). While there was no significant correlation between estimated preglomerular resistance and HbA1c, estimated postglomerular resistance correlated significantly and positively with HbA1c both in healthy subjects (r = 0.643, P = 0.013) and subjects with mild proteinuria (r = 0.589, P = 0.044). Glomerular filtration fraction, estimated Pglo and estimated postglomerular resistance in total subjects were associated significantly with HbA1c after adjustment for age, gender, and body mass index. These results demonstrate that, even in nondiabetic subjects, glycemic status is associated with estimated postglomerular resistance, but not estimated preglomerular resistance. It is suggested that increased estimated postglomerular resistance associated with higher HbA1c levels, even within the normal range, causes increased estimated Pglo, leading to increased FF. Thus, hemodynamic abnormalities associated with higher HbA1c levels may be related to glomerular hypertension, even in nondiabetic subjects.