Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses a-, b-, and g-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1b expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1b expression in the macula densa affects sodium excretion and saltsensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1b mRNA and protein were 30-and five-fold higher, respectively, than those of NOS1a in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1a-knockout (NOS1aKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P,0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P,0.01) fed a high-salt diet. These results indicate that NOS1b is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.
BackgroundType 2 diabetes mellitus (T2D), rapidly increasing to epidemic proportions, globally escalates cardiovascular disease risk. Although intensive interventions and comprehensive management of environmental risks factors for T2D are associated with reduced cardiovascular disease, such approaches are limited for individuals with high genetic T2D risk. In this study we investigated possible associations of ACE2 polymorphisms and cardiovascular risks in Uygur patients with T2D.Methods275 Uygur T2D patients and 272 non-diabetic Uygur individuals were enrolled as study participants. 14 ACE2 polymorphisms were genotyped by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry.ResultsACE2 SNP rs1978124, rs2048683, rs2074192, rs233575, rs4240157, rs4646156, rs4646188 and rs879922 were associated with T2D (all P < 0.05). The 8 diabetic risk related ACE2 SNPs were further associated with diabetic related cardiovascular complications or events but exhibited heterogeneity as fellows: firstly, almost all diabetic risk related ACE2 SNPs (all P < 0.05) were associated with increased SBP except rs1978124 and rs2074192, while rs2074192, rs4646188 and rs879922 were associated elevated DBP (all P < 0.05). Secondly, SNP rs4646188 was not correlated with any type of dyslipidemia (TRIG, HDL-C, LDL-C or CHOL), and the other 7 diabetic risk related loci were at least correlated with one type of dyslipidemia (all P < 0.05). In particular, rs879922 were simultaneously correlated with four type of dyslipidemia (all P < 0.05). Thirdly, ACE2 SNP rs2074192 and rs879922 were associated with carotid arteriosclerosis stenosis (CAS) ≥ 50% (both P < 0.05). Fourthly, ACE2 SNP rs2074192, rs4240157, rs4646188 and 879922 were associated with increased MAU (all P < 0.05). In addition, ACE2 SNP rs2048683, rs4240157, rs4646156, rs4646188 and rs879922 were linked to heavier LVMI (all P < 0.05), but only rs4240157, rs4646156 and rs4646188 were associated with lower LVEF (all P < 0.05).ConclusionACE2 SNP rs879922 may be a common genetic loci and optimal genetic susceptibility marker for T2D and T2D related cardiovascular risks in Uygurs.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0771-3) contains supplementary material, which is available to authorized users.
Women with gestational diabetes mellitus (GDM) have different gut microbiota in late pregnancy compared to women without GDM. It remains unclear whether alterations of gut microbiota can be identified prior to the diagnosis of GDM. This study characterized dynamic changes of gut microbiota from the first trimester (T1) to the second trimester (T2) and evaluated their relationship with later development of GDM. Compared with the control group (n = 103), the GDM group (n = 31) exhibited distinct dynamics of gut microbiota, evidenced by taxonomic, functional, and structural shifts from T1 to T2. Linear discriminant analysis (LDA) revealed that there were 10 taxa in T1 and 7 in T2 that differed in relative abundance between the GDM and control groups, including a consistent decrease in the levels of Coprococcus and Streptococcus in the GDM group. While the normoglycemic women exhibited substantial variations of gut microbiota from T1 to T2, their GDM-developing counterparts exhibited clearly reduced inter-time point shifts, as corroborated by the results of Wilcoxon signed-rank test and balance tree analysis. Moreover, cooccurrence network analysis revealed that the interbacterial interactions in the GDM group were minimal compared with those in the control group. In conclusion, lower numbers of dynamic changes in gut microbiota in the first half of pregnancy are associated with the development of GDM. IMPORTANCE GDM is one of the most common metabolic disorders during pregnancy and is associated with adverse short-term and long-term maternal and fetal outcomes. The aim of this study was to examine the connection between dynamic variations in gut microbiota and development of GDM. Whereas shifts in gut microbiota composition and function have been previously reported to be associated with GDM, very little is known regarding the early microbial changes that occur before the diagnosis of GDM. This study demonstrated that the dynamics in gut microbiota during the first half of pregnancy differed significantly between GDM and normoglycemic women. Our findings suggested that gut microbiota may potentially serve as an early biomarker for GDM.
The synergetic process of folliculogenesis is mainly regulated by GDF-9 and BMP-15 as well as their receptors, such as BMPR2, TβR1 and BMPR1B. Expressions of these factors and the receptors are significant different among species. This study was designed to detect expression of GDF-9, BMP-15 and their receptors in mouse, porcine and human healthy follicles by immunohistochemistry. Three ages of human ovary were studied according to ovarian developmental schedule, i.e. gestational week (GW) 16, puberty (14 year-old) and adult (40 year-old). The results showed that both GDF-9 and BMP-15 were detectable in oocytes from primary follicles onward, besides, BMP-15 also presented in granulosa cells (GCs) and follicular follicle of mature follicles in mouse. However, they were maintained in oocytes and GCs from primordial to mature follicles in porcine except that GDF-9 was undetectable in GCs of mature follicles. For human ovary, GDF-9 presented in oocytes of primordial follicles in all samples, whereas BMP-15 was only observed in primordial follicle of adult ovary. Receptors, BMPR2, TβR1 and BMPR1B were found in oocytes and GCs of all follicles in mouse and porcine. In human, they were stained in oocytes from primordial follices but BMPR1B was not expressed in pubertal primordial follicles. Furthermore, we found that GDF-9, BMP-15 and three receptors distributed in adult corpus lutea. Collectively, our studies suggested that GDF-9, BMP-15 and their receptors might correlate with primordial follicular recruitment in pig and human. Positive expression of the receptors (BMPR2, TβR1 and BMPR1B)in primordial follicles of mouse ovaries indicated that these receptors might interact with others ligands besides GDF-9 and BMP-15 to regulate primordial follicular activity in mouse. Moreover, presence of GDF-9 in oocytes and BMP-15 in oocytes and GCs of mature follicles from mice and porcine elucidated coordinated roles of GDF-9 and BMP-15 in cumulus oophorus expansion. Additionally, expression of these factors in adult human corpus lutea suggested they play roles in corpus luteum activity.
LOX-1 is a multifunctional membrane receptor that binds and internalizes oxidized LDL (oxLDL). We tested the hypothesis that blockade of LOX-1 with an anti-LOX-1 antibody limits nephropathy in male rats with diabetes and dyslipidemia (ZS rats; F(1) hybrid product of Zucker fatty diabetic rats and spontaneous hypertensive heart failure rats). Lean ZS rats were controls, while untreated obese ZS (OM), ZS obese rats injected with nonspecific rabbit IgG (OM-IgG; 2 microg intravenous injection given weekly), and obese ZS rats given anti-LOX-1 rabbit antibody (OM-Ab; 2 microg intravenous injection given weekly) were the experimental groups. The rats were treated from 6 to 21 wk of age. All obese groups had severe dyslipidemia and hyperglycemia. Kidneys of obese rats expressed LOX-1 in capillaries and tubules, were larger, accumulated lipid, had intense oxidative stress, leukocyte infiltration, depressed mitochondrial enzyme level and function, and peritubular fibrosis (all P < 0.05 vs. lean ZS rats). Injections with LOX-1 antibody limited these abnormalities (P < 0.01 vs. data in OM or OM-lgG rats). In vitro, renal epithelial LOX-1 expression was verified in a cultured proximal tubule cell line. Our study indicates that anti-LOX-1 (vascular and epithelial) therapy may effectively reverse critical pathogenic elements of nephropathy in diabetes and dyslipidemia.
Chronic aldosterone administration increases glomerular filtration rate (GFR) while inhibition of mineralocorticoid receptors (MR) markedly attenuates glomerular hyperfiltration and hypertension associated with primary aldosteronism or obesity. However, the mechanisms by which aldosterone alters GFR regulation are poorly understood. In the present study, we hypothesized that aldosterone suppresses tubuloglomerular feedback (TGF) via activation of macula densa (MD) MR. First, we observed the expression of MR in MD cells isolated by laser capture microdissection (LCM) and by immunofluorescence in rat kidneys. Second, to investigate the effects of aldosterone on TGF in vitro, we microdissected the juxtaglomerular apparatus (JGA) from rabbit kidneys and perfused the afferent arteriole (Af-Art) and distal tubule simultaneously. Under control conditions, TGF was 2.8 ± 0.2µm. In the presence of aldosterone (10−8 mol/L), TGF was reduced by 50%. The effect of aldosterone to attenuate TGF was blocked by the MR antagonist eplerenone (10−5 mol/L). Third, to investigate the effect of aldosterone on TGF in vivo, we performed micropuncture and TGF was determined by maximal changes in stop-flow pressure Psf (ΔPsf) when tubular perfusion rate was increased from 0 to 40 nl/min. Aldosterone (10−7 mol/L) decreased ΔPsf from 10.1 ± 1.4 to 7.7 ± 1.2 mmHg. In the presence of L-NG-monomethyl arginine citrate (L-NMMA, 10−3 mol/L), this effect was blocked. We conclude that MR are expressed in MD cells and can be activated by aldosterone, which increases nitric oxide (NO) production in the MD and blunts the TGF response.
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