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Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBRob/ob mice. Two cohorts of mice including appropriate controls were studied: i.e., diabetic mice that received oral carnosine supplementation (cohort 1) and human (h)CN1 transgenic (TG) diabetic mice (cohort 2). The lumen area ratio (LAR) of the afferent arterioles and glomerular parameters were measured by conventional histology. Three-dimensional analysis using a tissue clearing strategy was also used. In both cohorts, LAR was significantly larger in diabetic BTBRob/ob versus nondiabetic BTBRwt/ob mice (0.41?? 0.05 vs. 0.26 ?? 0.07, P < 0.0001 and 0.42 ?? 0.06 vs. 0.29 ?? 0.04, P < 0.0001) and associated with glomerular size (cohort 1: r = 0.55, P = 0.001 and cohort 2: r = 0.89, P < 0.0001). LAR was partially normalized by oral carnosine supplementation (0.34 ?? 0.05 vs. 0.41?? 0.05, P = 0.004) but did not differ between hCN1 TG and wild-type BTBRob/ob mice. In hCN1 TG mice, serum CN1 concentrations correlated with LAR (r = 0.90, P = 0.006). Diabetic mice displayed decreased nephrin expression and increased glomerular hypertrophy. This was not significantly different in hCN1 TG BTBRob/ob mice (P = 0.06 and P = 0.08, respectively). In conclusion, carnosine and CN1 may affect intraglomerular pressure in an opposing manner through the regulation of afferent arteriolar tone. This study corroborates previous findings on the role of carnosine in the progression of DKD. NEW & NOTEWORTHY Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBRob/ob mice. Our results provide evidence that carnosine feeding and CN1 overexpression likely affect intraglomerular pressure through vasoregulation of the afferent arteriole.

BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers.RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (PCONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection.PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Objective To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). Methods hCN1 transgenic (TG) mice were generated in a BTBROb/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBROb/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBROb/Ob mice. Results hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBROb/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumin-creatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBROb/Wt, BTBROb/Ob, and hCN1 BTBROb/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator–activated receptor-alpha have been reported to play essential roles in DKD. Conclusions Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. Key messages Increased carnosinase 1 (CN1) is associated with diabetic kidney disease (DKD). BTBROb/Ob mice with human CN1 develop a more aggravated DKD phenotype. Microarray revealed alterations by CN1 which are not altered by hyperglycemia. These genes have been described to play essential roles in DKD. Inhibiting CN1 could be beneficial in DKD.

How to effectively enhance the flame retardancy of polyamide 46/polyphenylene oxide (PA46/PPO) alloy is one of the key issues needed to be addressed. In this work, organic-modified zirconium phosphate (OZrP) nanosheet was incorporated with PU-coated carbon fiber (CF) to flame-retard PA46/PPO alloy. The combination of OZrP and CF showed an outstanding combination effect in improving the flame retardancy and thermal stability of PA46/PPO. With the incorporation of 2 wt% OZrP and 20 wt% CF, the peak heat release rate and peak smoke production rate of PA46/PPO were reduced by 65.6% and 86.2%, respectively. Besides, the Ti (temperature at 5% weight loss) and the residue of PA46/PPO/OZrP/CF were increased by 13.2 °C and 20.9 wt%, respectively, compared with PA46/PPO. The flame-retardant mechanism was further studied and revealed: when being burned, CF acted as the skeleton to improve the strength of char; simultaneously, OZrP catalyzed the carbonization of the polymer chains on the CF surface to form a strong and compact protective char layer, which blocked the transmission of heat and combustible gases, thus effectively improved the flame retardancy of the composite.

This study assessed if serum carnosinase (CNDP1) activity and concentration in patients with type 2 diabetes mellitus (T2D) with diabetic nephropathy (DN) differs from those without nephropathy. In a cross-sectional design 127 patients with T2D with DN ((CTG)5 homozygous patients n = 45) and 145 patients with T2D without nephropathy ((CTG)5 homozygous patients n = 47) were recruited. Univariate and multivariate regression analyses were performed to predict factors relevant for serum CNDP1 concentration. CNDP1 (CTG)5 homozygous patients with T2D with DN had significantly lower CNDP1 concentrations (30.4 ± 18.3 vs 51.2 ± 17.6 µg/ml, p

Low serum carnosinase (CN-1) concentrations are associated with low risk for development of diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). Although CN-1 is expressed in the kidney, urinary CN-1 (CNU) excretion and its pathological relevance in patients with T2D have not been investigated to date. The present study therefore assessed the extent of CNU excretion in healthy subjects (n = 243) and in patients with T2D (n = 361) enrolled in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1) in relation to functional renal parameters. CNU was detected in a high proportion of healthy individuals, 180 (74%); median CNU excretion was 0.25 mg/24 h [(IQR 0–0.65 mg/24 h]. In patients with T2D the prevalence and extent of CNU increased in parallel with albuminuria (r = 0.59, p p p n = 241), micro- (n = 80) and macroalbuminuria (n = 40), respectively). Patients with estimated glomerular filtration rate (eGFR) 90 ml/min/1.73 m2) (1.36 vs 0.13 mg/24 h, p R2 = 0.37, p

Background: Among persons with type 1 diabetes mellitus (T1DM) low concentrations of magnesium have been reported. Previous (small) studies also suggested a relation of hypomagnesemia with (poor) glycaemic control and complications. We aimed to investigate the magnitude of hypomagnesemia and the associations between magnesium with parameters of routine T1DM care in a population of unselected outpatients. Methods: As part of a prospective cohort study, initially designed to measure quality of life and oxidative stress, data from 207 patients with a mean age of 45 [standard deviation (SD) 12] years, 58% male, diabetes duration 22 [interquartile range (IQR) 16, 31] years and glycated haemoglobin (HbA1c) of 60 (SD 11) mmol/mol [7.6 (SD 1.0)%] were examined. Hypomagnesemia was defined as a concentration below Results: Mean magnesium concentration was 0.78 (SD 0.05) mmol/l. A deficiency was present in 4.3% of participants. Among these persons, mean concentration was 0.66 (SD 0.03) mmol/l. There was no correlation between magnesium and HbA1c at baseline ( r = –0.014, p = 0.843). In multivariable analysis, free thiols (reflecting the degree of oxidative stress) were significantly and negatively associated with magnesium concentrations. Conclusion: In this cohort of T1DM outpatients, the presence of hypomagnesemia was infrequent and, if present, relative mild. Magnesium was not associated with glycaemic control nor with presence of micro- and macrovascular complications. Although these results need confirmation, in particular the negative association of magnesium with free thiols, this suggests that hypomagnesemia is not a relevant topic in routine care for people with T1DM.

The free-radical trapping capability of buckminsterfullerene (C60) inevitably inhibits peroxide vulcanization, which is one of the most challenges for its application in high temperature vulcanized silicone rubber (HTVSR). In this work, polymethylphenylsiloxane decorated C60 (PMPS-d-C60) was fabricated via π-π stacking interaction and incorporated into HTVSR. It was found that PMPS-d-C60 not only overcame the negative effect of C60 on HTVSR vulcanization, but also effectively enhanced the flame retardancy of HTVSR. By adding only 4.0 phr PMPS-d-C60, the limiting oxygen index of HTVSR was increased to 29.0%, and its peak of heat release rate was reduced more than 32%.

How to effectively improve tracking resistance and flame retardancy of silicone rubber is one of the key problems needed to be resolved in the development of high performance silicone rubber insulating materials. In this work, a novel functional silane containing hindered amine and urethane groups, named PPAS, was synthesized by using 1,2,2,6,6-pentamethyl-4-piperidinol, (3-isocyanatopropyl) triethoxysilane and allyl acohol via the nucleophilic substitution and trans -etherification. The effects of PPAS on the tracking resistance, flame retardancy and thermal stability of addition-cure liquid silicone rubber (ALSR) were investigated. It was found that PPAS could effectively enhance the tracking resistance and flame retardancy of ALSR simultaneously. When the content of PPAS was only 3.0 phr, ALSR/PPAS could pass the 1A4.5 kV level in the inclined plane (IP) test and had outstanding electrical erosion resistance, which showed great potential in exterior insulator. In particular, the limiting oxygen index (LOI) of the ALSR/PPAS was 30.0%, and it had a good self-extinguishing capability. Meanwhile, the risk of fire measured by cone calorimeter was also significantly reduced. The mechanism for these phenomena were further studied and revealed: PPAS could effectively quench the peroxyl radicals and suppress the oxidation degradation of Si-CH 3 groups, eliminate the Si-OH groups and promote the cross-linked reaction during the thermal degradation of ALSR.

Background. Carnosinase-1 (CN-1) can be detected in 24 h urine of healthy individuals and patients with type 2 diabetes (T2DM). We aimed to assess whether urinary CN-1 is also reliably measured in spot urine and investigated its association with renal function and the albumin/creatinine ratio (ACR). We also assessed associations between theCNDP1(CTG)ngenotype and CN-1 concentrations in serum and urine.Methods. Patients with T2DM (n=85) and nondiabetic patients with chronic kidney disease (CKD) (n=26) stratified by albuminuria (ACR≤300 mg/gorACR>300 mg/g) recruited from the nephrology clinic and healthy subjects (n=24) were studied.Results. Urinary CN-1 was more frequently detected and displayed higher concentrations in patients withACR>300 mg/gas compared to those withACR≤300 mg/girrespective of the baseline disease (T2DM: 554 ng/ml [IQR 212-934 ng/ml] vs. 31 ng/ml [IQR 31-63 ng/ml] (p<0.0001) and nondiabetic CKD: 197 ng/ml [IQR 112-739] vs. 31 ng/ml [IQR 31-226 ng/ml] (p=0.015)). A positive correlation between urinary CN-1 and ACR was found (r=0.68,p<0.0001). Multivariate linear regression analysis revealed that ACR and serum CN-1 concentrations but not eGFR or the CNDP1 genotype are independent predictors of urinary CN-1, explaining 47% of variation of urinary CN-1 concentrations (R2=0.47,p<0.0001).Conclusion. These results confirm and extend previous findings on urinary CN-1 concentrations, suggesting that assessment of CN-1 in spot urine is as reliable as in 24 h urine and may indicate that urinary CN-1 in macroalbuminuric patients is primarily serum-derived and not locally produced.

To promote the application of silicone rubber in the electronics industry, it is urgent to improve its thermal stability and flame retardancy. In this work, iron oxide nanoparticle in-situ decorated boron nitride nanosheet (FeBN) was fabricated via sol–gel method and then incorporated into addition-cure liquid silicone rubber (ALSR). It was found that FeBN uniformly dispersed in polymer and effectively improved the thermal stability and flame retardancy of ALSR. With only 2.0 phr FeBN, the T10 and LOI of ALSR were increased to 438.2 °C and 28.5%, respectively, which was attributed to the synergism of free-radical quenching capability and layer barrier effect.

How to effectively improve the flame retardancy of polypropylene (PP) is one of the key problems needed to be resolved to promote its development and application. In this work, an efficient synergist—N-alkoxy hindered amine (NOR116) was combined with a novel intumescent flame retardant (IFR, i.e., ammonium polyphosphate/silicone-containing macromolecular charring agent) to flame-retard PP. The effects of NOR116 on the thermal degradation and combustion behavior of the PP/IFR composites were investigated. It was found that a small amount of NOR116 could effectively improve the flame retardancy and thermal stability of the composites. When the content of NOR116 was 0.3 wt%, the limiting oxygen index (LOI) value of the composite was increased from 35.0% to 42.5%, and the vertical burning (UL-94) test reached a V-0 rating. Meanwhile, the heat release rate (HRR), total heat release (THR), average mass loss rate (av-MLR) and smoke production rate (SPR) of the composite were also significantly reduced. Thermogravimetric analysis (TGA), Thermogravimetry-Fourier transform infrared spectrometry (TG-FTIR), scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDXS) and Laser Raman Spectroscopy (LRS) results revealed that NOR116 could change the thermal degradation of the PP/IFR composites, and promote the charring performance of IFR at lower temperature and enhance the quantity and quality of the intumescent char at high temperature. The possible synergistic mechanism between NOR116 and IFR in PP was also discussed.

Free radicals play a negative role during the thermal degradation of silicone rubber (SR). Quenching free radicals is proposed to be an efficient way to improve the thermal-oxidative stability of SR. In this work, a novel zirconium-containing polyhedral oligometallasilsesquioxane (Zr-POSS) with free-radical quenching capability was synthesized and characterized. The incorporation of Zr-POSS effectively improved the thermal-oxidative stability of SR. The T5 (temperature at 5% weight loss) of SR/Zr-POSS significantly increased by 31.7 °C when compared to the unmodified SR. Notably, after aging 12 h at 280 °C, SR/Zr-POSS was still retaining about 65%, 60%, 75%, and 100% of the tensile strength, tear strength, elongation at break, and hardness before aging, respectively, while the mechanical properties of the unmodified SR were significantly decreased. The possible mechanism of Zr-POSS for improving the thermal-oxidative stability of SR was intensively studied and it was revealed that the POSS structure could act as a limiting point to suppress the random scission reaction of backbone. Furthermore, Zr could quench the free radicals by its empty orbital and transformation of valence states. Therefore, it effectively suppressed the thermal-oxidative degradation and crosslinking reaction of the side chains.

Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a K-i of 11nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naive CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.

Considering that the homozygous CNDP1 (CTG)5 genotype affords protection against diabetic nephropathy (DN) in female patients with type 2 diabetes, this study assessed if this association remains gender-specific when applying clinical inclusion criteria (CIC-DN) or biopsy proof (BP-DN). Additionally, it assessed if the prevalence of the protective genotype changes with diabetes duration and time on hemodialysis and if this occurs in association with serum carnosinase (CN-1) activity. Whereas the distribution of the (CTG)5 homozygous genotype in the no-DN and CIC-DN patients was comparable, a lower frequency was found in the BP-DN patients, particularly in females. We observed a significant trend towards high frequencies of the (CTG)5 homozygous genotype with increased time on dialysis. This was also observed for diabetes duration but only reached significance when both (CTG)5 homo- and heterozygous patients were included. CN-1 activity negatively correlated with time on hemodialysis and was lower in (CTG)5 homozygous patients. The latter remained significant in female subjects after gender stratification. We confirm the association between the CNDP1 genotype and DN to be likely gender-specific. Although our data also suggest that (CTG)5 homozygous patients may have a survival advantage on dialysis and in diabetes, this hypothesis needs to be confirmed in a prospective cohort study.

We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman’s capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

How to improve the flame-retardant efficiency and dispersion of layered double hydroxide (LDH) in silicone rubber (SR) is one of the biggest challenges for the application of halogen-free flame retardant SR/LDH nanocomposite. In this work, a novel and highly efficient flame retardant, i.e., polyborosiloxane decorated layered double hydroxide (PBS-d-LDH), was synthesized and incorporated into SR to prepare SR/PBS-d-LDH nanocomposite. Benefitting from the sulfonate and boron hydroxyl groups of PBS, PBS-d-LDH was easily exfoliated and dispersed in SR. PBS-d-LDH endowed SR with outstanding mechanical properties, thermal stability, flame retardancy and smoke suppression performance. When the content of PBS-d-LDH was only 5.0 phr, SR/PBS-d-LDH had a good self-extinguishing capability, and its peak heat release rate and peak smoke production rate were reduced by 54.4% and 61.5%, respectively. Furthermore, the Ti (temperature at 5% weight loss) and the residue of SR/PBS-d-LDH at 700 °C were increased by 37.0 °C and 23.5 wt%, respectively. The mechanism analysis revealed that when being burned, the crosslinking reaction of PBS and layer barrier effect of LDH showed a good synergism in the ceramization of condensed phase, which contributed to the prominent flame retardancy and smoke suppression of the SR/PBS-d-LDH nanocomposite. This work provides a promising strategy to prepare highly efficient flame retardant polymer.