Search

Abstract Nobiletin has protective effects on cardiovascular diseases, but the mechanism is not clear. In this study, we examined whether nobiletin affects the expression of miR-590/LPL and its relative effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. RT-qPCR analysis showed that nobiletin increased the expression of miR-590. Western blot analysis showed that nobiletin-suppressed LPL expression was enhanced by miR-590 mimic and abrogated by miR-590 inhibitor. Oil Red O staining and high-performance liquid chromatography assays showed that nobiletin attenuated lipid accumulation in macrophages. Treatment with nobiletin and miR-590 mimic decreased cellular lipid accumulation, whereas treatment with miR-590 inhibitor increased cellular lipid accumulation. ELISA illustrated that nobiletin alleviated pro-inflammatory cytokine secretion in macrophages as measured by, which was reduced by miR-590 mimic and increased by miR-590 inhibitor. In conclusion, nobiletin may alleviate lipid accumulation and secretion of pro-inflammatory cytokines by enhancing the inhibitory effect of miR-590 on LPL expression, suggesting a promising strategy for potential drug development for atherosclerosis. Highlights • Nobiletin may alleviate lipid accumulation in human THP-1 macrophages. • Nobiletin may alleviate secretion of pro-inflammatory cytokines in human THP-1 macrophages. • Nobiletin may enhance the inhibitory effect of miR-590 on LPL expression. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) have been attributed to genetic and environmental factors. However, monogenic and copy number variations cannot sufficiently explain the cause of the majority of CAKUT cases. Multiple genes through various modes of inheritance may lead to CAKUT pathogenesis. We previously showed that Robo2 and Gen1 coregulated the germination of ureteral buds (UB), significantly increasing CAKUT incidence. Furthermore, MAPK/ERK pathway activation is the central mechanism of these two genes. Thus, we explored the effect of the MAPK/ERK inhibitor U0126 in the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice. Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice. Additionally, a single dose of 30 mg/kg U0126 on day 10.5 embryos (E10.5) was most effective for reducing CAKUT incidence and ectopic UB outgrowth in Robo2 PB/+ Gen1 PB/+ mice. Furthermore, embryonic kidney mesenchymal levels of p-ERK were significantly decreased on day E11.5 after U0126 treatment, along with decreased cell proliferation index PHH3 and ETV5 expression. Collectively, Gen1 and Robo2 exacerbated the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice through the MAPK/ERK pathway, increasing proliferation and ectopic UB outgrowth. • Urinary system congenital anomalies are genetically and environmentally complex. • ROBO2 and GEN1 coregulate ureteral bud germination and influence CAKUT incidence. • U0126 treatment reduces CAKUT incidence in mice with Robo2 and Gen1 mutations. • We conclude that ROBO2 and GEN1 influence MAPK/ERK signaling to contribute to CAKUT. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p -ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM. • GDM could contribute to the manifestation of CAKUT in mice. • Ectopic UBs and extended length of CNDs were noted in the metanephric development stage under GDM. • GDM could alter the RET/MAPK/ERK pathway involved in metanephric development. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) are a family of often-concurrent diseases with various anatomical spectra. Null-mutant Gen1 mice frequently develop multiple urinary phenotypes, most commonly duplex kidneys, and are ideal subjects for research on ectopic budding in CAKUT development. The upper and lower kidney poles of the Gen1 PB/PB mouse were examined by histology, immunofluorescence, and immunohistochemistry. The newborn Gen1 PB/PB mouse lower poles were significantly more hypoplastic than the corresponding upper poles, with significantly fewer glomeruli. On embryonic day 14.5, immediately before first urine formation, the upper pole kidney was already larger than the lower pole kidney. In vivo and in vitro, embryonic kidney upper poles had more ureteric buds than lower poles. Gen1 PB/PB embryos exhibited ectopic ureteric buds, usually near the original budding site, occasionally far away, or, rarely, derived from the primary budding site. Therefore, ectopia of the ureteric buds is the core of CAKUT formation. Further studies will be needed to investigate the regulatory roles of these genes in initial ureteric budding and subsequent ontogenesis during metanephros development. • Ectopia of the initial budding is central to the formation of CAKUT. • Three kinds of ectopic bud develop into three duplex kidneys in Gen1 PB/PB mice. • Upper pole kidney of newborn Gen1 PB/PB mice was more hypoplastic than that in lower. • At E14.5, the upper pole kidney was already larger than the lower pole kidney. • Ectopic budding alone results in kidney hypoplasia, not dysplasia in Gen1 mutation. [ABSTRACT FROM AUTHOR]

Proteinuria is an important marker and is closely related to the progressive decline of renal function. Our previous research showed that angiopoietin-like-3 (ANGPTL3) plays a crucial role in proteinuria. In this study, we prepared an antibody against ANGPTL3 coil-coiled domain (ANGPTL3-CCD) and investigated the protective effect of anti -ANGPTL3-CCD antibody in mice with adriamycin-induced nephropathy. Nephropathy was established by adriamycin injection at a dose of 25 mg per kg in 8–12 week-old male mice in the ADR group. Blockade of ANGPTL3 by anti -ANGPTL3-CCD antibody (20 mg per kg) was performed every three days nine times after adriamycin injection in the ADR plus anti -angptl3-antibody group. The anti -ANGPTL3-CCD antibody can specifically recognize ANGPTL3. After anti -ANGPTL3-CCD antibody intervention, the urinary protein level in the ADR plus anti -angptl3-antibody group was significantly lower than that in the ADR group. Serum albumin was higher and triglyceride and total cholesterol were lower in the ADR plus anti -angptl3-antibody group than in the ADR group. The levels of serum creatinine did not significantly differ among the groups. Focal sclerotic glomeruli and podocyte foot processes extensive fusion were found in the renal tissue of the ADR group, whereas no sclerotic glomeruli and only partial fusion were found in the ADR plus anti -angptl3-antibody group. This study demonstrated that the anti -ANGPTL3-CCD antibody ameliorated proteinuria and podocyte dysfunction in adriamycin-induced nephropathy in mice. • ANGPTL3 is considered to be an important molecules involved in proteinuria. • Anti -ANGPTL3-CCD antibody decreased serum lipid levels. • Anti -ANGPTL3-CCD antibody ameliorated proteinuria and podocyte injury in adriamycin-induced nephropathy mice. [ABSTRACT FROM AUTHOR]

Intrauterine low-protein diet can affect kidney development and hence final nephron number. In this study, we reported that intrauterine low-protein diet can cause congenital anomalies of the kidney and urinary tract (CAKUT) phenotypes, which was dominated by the duplicated collecting system phenotype. At the same time, ectopic ureteric buds were increased under intrauterine low-protein diet and the number of UB branches was reduced in the serum-free culture. Intrauterine low-protein diet can change metanephric gene expression. Slit2/Robo2 and Spry1 expression levels were decreased, Ret expression was increased, and downstream p -Akt activity enhanced with apoptosis abnormal in ureteric bud tissue, which may be the mechanisms that intrauterine low-protein diet causes increased incidence of CAKUT in offspring. Thus, we showed correlation between intrauterine low-protein diet and CAKUT in offspring. • Intrauterine low-protein diet can cause CAKUT, which was dominated by the duplicated collecting system phenotype. • Ectopic ureteric buds were increased under intrauterine low-protein diet. • The number of UB branches was reduced in the serum-free culture. • Intrauterine low-protein diet can change metanephric gene expression. [ABSTRACT FROM AUTHOR]