Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Sirtuin 1 (Sirt1), a NAD[superscript +]-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.Japan. Ministry of Education, Culture, Sports, Science and Technology (Grant 22790800

Physical, behavioral, and hormonal changes in the resumption of sexual receptivity during postpartum infertility in female bonobos at Wamba

The operational sex ratio (OSR) is used as a predictor for the intensity of mating competition. While many factors affect the OSR, there tends to be a high male bias in primate species with long interbirth intervals and non-seasonal breeding, such as hominid apes. However, the OSR of bonobos (Pan paniscus) is lower than that of chimpanzees (Pan troglodytes), which is thought to reduce competitive and aggressive male behaviors. The low OSR of bonobos is considered to result from the early resumption of female sexual receptivity during postpartum infertility and the receptivity that they continue to show until the late stage of pregnancy. In this study, we aimed to examine the early resumption of sexual receptivity by providing quantitative data on the resumption of maximal swelling (MS) in sexual skin and copulation, and changes in urinary estrone conjugate (E1C) concentrations during postpartum infertility in wild bonobos at Wamba in the Luo Scientific Reserve, Democratic Republic of the Congo. An analysis of 9 years of data revealed that females showed the first MS at 225.4 +/- 132.7 days after parturition and performed the first copulation at 186.8 +/- 137.5 days after parturition, both of which were in the early stage of postpartum infertility. The proportion of days with MS and the frequency of copulation steadily increased subsequently; however, the rate of increase gradually slowed approximately 42-48 months after parturition. There was a significant correlation between the proportion of days with MS and the frequency of copulation in each period for each female. We confirmed that E1C concentrations were significantly higher during the MS phase than during the non-MS phase. Data collected over 15 months on the E1C concentration during MS showed that it increased linearly from the early stage of lactation to the next conception. These results suggest that, although female bonobos do not usually conceive until 49.7 months after parturition, they resume MS and receptivity at a low level of E1C concentration during an early stage of postpartum infertility. This study of female bonobo receptivity and sex hormone changes during the postpartum non-fertile period provides important insights for examining the evolution of low OSR, which has been considered to contribute to peaceful social relationships among bonobos

Do female bonobos (Pan paniscus) disperse at the onset of puberty? Hormonal and behavioral changes related to their dispersal timing

Natal dispersal is a milestone in an animal's life history, but its timing in developmental trajectories may differ between species. Although the two Pan species exhibit a similar pattern of female-biased dispersal, female bonobos (P. paniscus) leave their natal groups at an earlier age than female chimpanzees (P. troglodytes). As a preliminary step to explore the dispersal strategies of female bonobos, this study aimed to determine the relations of sexual swelling development, behavioral and hormonal activation, and first ovulation relative to dispersal timing. We measured levels of urinary estrone conjugates (E1C) and pregnanediol glucuronide (PdG) from 14 nulliparous females in wild bonobo groups at Wamba in the Democratic Republic of the Congo, and recorded their copulations with mature males. When close to dispersal, female bonobos exhibited swelling of the sexual skin (labia minora and perianal region) that did not reach the mature stage. Urinary E1C levels and copulation rates increased slightly before dispersal and greatly increased after dispersal. Ovulatory or gestatory signs implied by daily hormone profiles were not detected until one to two years after dispersal. Our findings indicate that female bonobos disperse at an early pubertal stage before ovulatory cycling is established. This earlier dispersal than sexual maturation could allow female bonobos to postpone reproduction-related energy costs until they become familiar with their new group or gain more time finding the group more suitable for successful reproduction in the future before actually settling. Further demographic and genetic data from dispersal to reproduction will help clarify their dispersal strategies

Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone

Steroidal anti-inflammatory drugs are widely used for the treatment of chronic cutaneous inflammation, such as atopic dermatitis, although it remains unknown how they modulate cutaneous mast cell functions. We investigated the effects of prolonged treatment with a synthetic glucocorticoid, dexamethasone, on murine connective tissue-type mast cells using in vitro and in vivo models. Our connective tissue-type bone marrow-derived cultured mast cell model was found to be sensitive to mast cell secretagogues, such as compound 48/80 and substance P, and higher expression levels of α subunit of a trimeric G protein, Gi1, and several Mas-related G protein-coupled receptor (Mrgpr) subtypes were observed in comparison with immature cultured mast cells. Secretagogue-induced degranulation and up-regulation of these genes was suppressed when cultured in the presence of dexamethasone. The profiles of granule constituents were drastically altered by dexamethasone. Topical application of dexamethasone down-modulated secretagogue-induced degranulation and the expression levels of several Mrgpr subtypes in cutaneous tissue. These results suggest that mast cell-mediated IgE-independent cutaneous inflammation could be suppressed by steroidal anti-inflammatory drugs through the down-regulation of G αi1 and several Mrgpr subtypes in mast cells

Triglyceride content in remnant lipoproteins is significantly increased after food intake and is associated with plasma lipoprotein lipase.

BackgroundPrevious large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma.MethodsTG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal.ResultsRLP-TG/TG ratio (concentration) and RLP-TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal.ConclusionsConcentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma

Effect of Charged Group Spacer Length on Hydration State in Zwitterionic Poly(sulfobetaine) Brushes

Effect of alkyl chain spacer length between the charged groups (CSL) in zwitterionic poly­(sulfobetaine) (PSB) brushes on the hydration state was investigated. PSB brushes with ethyl (PMAES), propyl (PMAPS), or butyl (PMABS) CSL were prepared by surface-initiated atom transfer radical polymerization on silicon wafers. Hydration states of the PSB brushes in aqueous solutions and/or humid vapor were investigated by contact angle measurement, infrared spectroscopy, AFM observation, and neutron reflectivity. The PSB brushes are swollen in humid air and deionized water due to the hydration of the charged groups leading to the reduction of hydrated PSB brushes/water interfacial free energy. The hydrated PSB brushes exhibit clear interface with low interfacial roughness due to networking of the PSB brush chains through association of the SBs. The hydrated PSB brushes produce diffusive swollen layer in the presence of NaCl because of the charge screening followed by SB dissociation by the bound ions. The ionic strength sensitivity in the hydration got more significant with increasing the CSL in SBs because of the augmentation in partial charge by charged group separation

Lipoprotein lipase does not increase significantly in the postprandial plasma.

BackgroundPrevious reports have shown that lipoprotein lipase (LPL) activity significantly increases in the postprandial plasma associated with the increase of TG-rich lipoproteins. Therefore, we have reexamined those relationships using newly developed LPL assay with the different kinds of food intake.MethodsStandard meal (n=81), 50g of fat (n=54), 75g of glucose (n=25) and cookie (25g fat and 75g carbohydrate fat) (n=28) were administered in generally healthy volunteers. Plasma LPL, HTGL and TC, TG, LDL-C, HDL-C, RLP-C and RLP-TG were determined at subsequent withdrawal after the food intake.ResultsPlasma TG, RLP-C and RLP-TG were significantly increased at 8PM (2h after dinner of standard meal) compared with 8AM before breakfast within the same day. Also those parameters were significantly increased in 2-6h after fat load. However, the concentrations and activities of LPL and HTGL did not significantly increase in association with an increase in the TG and remnant lipoproteins. Also LPL concentration did not significantly increase after glucose and "cookie test" within 4h.ConclusionNo significant increase of LPL activity was found at CM and VLDL overload after different kinds of food intake when reexamined by newly developed assay for LPL activity and concentration