The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in ...progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload.
We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers.
The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis.
The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.
•SGLT2 inhibition suppresses renal proximal tubule megalin O-GlcNAcylation.•Diminished O-GlcNAcylation promotes proximal tubule megalin internalization.•Proximal tubule megalin internalization reduces its endocytic function.•Reduced megalin endocytic function ameliorates renal protein overload in diabetes.•Amelioration of protein overload attenuates proximal tubule mitochondrial injury.
Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 ...deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.
Although the measurement of hemoglobin A1c (HbA1c) using high-performance liquid chromatography (HPLC) is routinely used to estimate average blood glucose levels, it may not be accurately measured ...for various reasons, such as alteration of red blood cell lifespan and the existence of hemoglobin variants; including hemoglobin F (HbF). Here, we report cases of fulminant type 1 and type 2 diabetes mellitus in which HbA1c levels were unmeasurable because of increased labile HbA1c levels. Case 1 involved a 73-year-old man with fulminant type 1 diabetes mellitus, who was brought to our hospital with diabetic ketoacidosis. The patient’s blood glucose level was 994 mg/dL, and HbA1c was unmeasurable, which turned out to be 6.2% on the next day when the blood glucose level was normalized. Case 2 involved a 72-year-old man with type 2 diabetes mellitus, whose blood glucose level was 767 mg/dL, and HbA1c was unmeasurable, which turned out to be 17.9% the following day. In both cases, the chromatograms showed that the HbA1c peaks overlapped with large labile HbA1c peaks, which decreased the next day. It is important to keep in mind that HbA1c levels may not be accurately measured in cases of extreme hyperglycemia because of an increase in labile HbA1c, regardless of the absolute HbA1c level.
We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus ...patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% 95% CI: -49.2%, -9.8% between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.
A concise asymmetric transfer hydrogenation of diaryl ketones, promoted by bifunctional Ru complexes with an etherial linkage between 1,2-diphenylethylenediamine (DPEN) and η6-arene ligands, was ...successfully developed. Because of the effective discrimination of substituents at the ortho position on the aryl group, unsymmetrical benzophenones were smoothly reduced in a 5:2 mixture of formic acid and triethylamine with an unprecedented level of excellent enantioselectivity. For the non-ortho-substituted benzophenones, the oxo-tethered catalyst electronically discerned biased substrates, resulting in attractive performance yielding chiral diarylmethanols with >99% ee.
An efficient method for the synthesis of N‐(hetero)arylcarbazoles, useful compounds for functional materials, is reported. Various (hetero)aryl chlorides reacted with N‐carbazolylmagnesium chloride ...in the presence of a palladium catalyst (0.05 to 0.2 mol%) prepared from allylpalladium(II) chloride dimer {PdCl(allyl)2} and di‐tert‐butyl(2,2‐diphenyl‐1‐methylcyclopropan‐1‐yl)phosphine (cBRIDP) under mild conditions (110 °C) in a short period of time (15 min to 2 h) to give N‐(hetero)arylcarbazoles in high yields. The reactions of bromochlorobenzenes proceeded in favour of the bromo group to afford N‐(chlorophenyl)carbazoles in a highly selective manner. Functional materials for use in organic light‐emitting diodes, such as mCP, 26mcPy, CBP and TCB, were also obtained in high yields within 15 min by the reaction of (hetero)aryl polyhalides. Optimization of the reaction conditions and a postulated catalytic cycle for the reaction are also discussed.
New pincer ruthenium complexes bearing a monodentate N-heterocyclic carbene ligand were synthesized and demonstrated as powerful hydrogenation catalysts. With an atmospheric pressure of hydrogen gas, ...aromatic, heteroaromatic, and aliphatic esters as well as lactones were converted into the corresponding alcohols at 50 °C. This reaction protocol offers reliable access to alcohols using an easy operational setup.
The use of methanol for the selective methylation of aromatic amines with RuHCl(CO)(PN
P) (PN
P = bis(2-diphenylphosphinoethyl)amine) is reported. Various aromatic amines were transformed into their ...corresponding monomethylated secondary amines in high yields at 150 °C with a very low catalyst loading (0.02-0.1 mol %) in the presence of KO
Bu (20-60 mol %). The catalyst precursor, RuHCl(CO)(PN
P), was converted to RuH(CO)
(PN
P)
under the catalytic conditions and also serves as a highly effective catalyst. The robustness of this catalyst contributes to its outstanding catalytic activity, even under reaction conditions, in which CO is liberated from methanol.
PDF
