scholarly journals Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fang-Zheng Wang ◽  
Hong Zhou ◽  
Hong-Yu Wang ◽  
Hang-Bing Dai ◽  
Qing Gao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Hydrogen Sulfide ◽  
Calcium Deposition ◽  
Control Group ◽  
Sprague Dawley ◽  
Sodium Hydrosulfide ◽  
Key Factor ◽  
Tgf Β1 ◽  
Arterial Medial Calcification ◽  
Medial Calcification

Abstract Background Arterial medial calcification (AMC) is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes and chronic kidney disease. Here, we tested whether hydrogen sulfide (H2S) can prevent AMC in rats with diabetic nephropathy (DN). Methods DN was induced by a single injection of streptozotocin and high-fat diet (45% kcal as fat) containing 0.75% adenine in Sprague–Dawley rats for 8 weeks. Results Rats with DN displayed obvious calcification in aorta, and this was significantly alleviated by Sodium Hydrosulfide (NaHS, a H2S donor, 50 μmol/kg/day for 8 weeks) treatment through decreasing calcium and phosphorus content, ALP activity and calcium deposition in aorta. Interestingly, the main endogenous H2S generating enzyme activity and protein expression of cystathionine-γ-lyase (CSE) were largely reduced in the arterial wall of DN rats. Exogenous NaHS treatment restored CSE activity and its expression, inhibited aortic osteogenic transformation by upregulating phenotypic markers of smooth muscle cells SMα-actin and SM22α, and downregulating core binding factor α-1 (Cbfα-1, a key factor for bone formation), protein expressions in rats with DN when compared to the control group. NaHS administration also significantly reduced Stat3 activation, cathepsin S (CAS) activity and TGF-β1 protein level, and improved aortic elastin expression. Conclusions H2S may have a clinical significance for treating AMC in people with DN by reducing Stat3 activation, CAS activity, TGF-β1 level and increasing local elastin level.

scholarly journals Liraglutide Regulates the Kidney and Liver in Diabetic Nephropathy Rats through the miR-34a/SIRT1 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Shan Xiao ◽  
Ye Yang ◽  
Yue-Tong Liu ◽  
Jun Zhu
Keyword(s):  
Electron Microscopy ◽  
Diabetic Nephropathy ◽  
Treated Group ◽  
Protective Role ◽  
Control Group ◽  
Related Factors ◽  
Qrt Pcr ◽  
Regulatory Effects ◽  
Tgf Β1 ◽  
Liver Tissues

Purpose. To explore the regulatory effects of liraglutide on the kidney and liver through the miR-34a/SIRT1 pathway with related factors in diabetic nephropathy (DN) rats. Methods. DN rats were randomly divided into two groups ( n = 10 ) and were injected with liraglutide or normal saline twice a day. The 24-hour urine microalbumin content and biochemical index levels were measured. qRT-PCR was performed to detect the expression of miR-34a in the kidney and liver tissues. The levels of SIRT1, HIF-1a, Egr-1, and TGF-β1 in kidney and liver tissues were determined using qRT-PCR, western blot, and immunohistochemistry. Electron microscopy and HE staining were used to observe the ultrastructure and pathological changes. Results. Liraglutide treatment in DN rats decreased blood glucose, 24-hour urine microalbumin, TC, TG, LDL-C, UA, Cr, UREA, ALT, and AST levels and increased the level of HDL-C ( P < 0.05 ). Compared with the control group, the miR-34a levels were significantly decreased in kidney and liver tissues followed by liraglutide treatment ( P < 0.05 ). The levels of SIRT1 in the liraglutide group are significantly higher than those in the control group with the kidney and liver tissues ( P < 0.05 ). Conversely, the contents of HIF-1a, Egr-1, and TGF-β1 were significantly lower in the liraglutide group than in the control group ( P < 0.05 ). Electron microscopy showed that the kidney of the liraglutide-treated group exhibited minor broadening of the mesangial areas, fewer deposits, and a well-organized foot process. HE staining revealed that the kidney of the liraglutide-treated rats had a more regular morphology of the glomerulus and Bowman sac cavity and lighter tubular edema. Additionally, the liraglutide-treated DN rats had a clear hepatic structure, a lower degree of steatosis, and mild inflammatory cell infiltration. Conclusion. Liraglutide, through its effect on the miR-34a/SIRT1 pathway, may have a protective role in the kidney and liver of DN rats.

scholarly journals Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway

2019 ◽  
Vol 20 (17) ◽  
pp. 4202 ◽  
Author(s):  
Ye-Bo Zhou ◽  
Hong Zhou ◽  
Li Li ◽  
Ying Kang ◽  
Xu Cao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Smooth Muscle Cells ◽  
Vascular Calcification ◽  
High Glucose ◽  
Muscle Cells ◽  
Calcium Deposition ◽  
Cathepsin S ◽  
Key Factor ◽  
Factor Α

Vascular calcification can be enhanced by hyperglycemia. Elastin loss in tunica media promotes the osteogenic transformation of smooth muscle cells (SMCs) and involves arterial medial calcification (AMC) that is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes. Here, we tested whether hydrogen sulfide (H2S), an endogenous gaseous mediator, can prevent elastin loss and attenuate calcification induced by high glucose in SMCs. Calcification was induced by high glucose (4500 mg/L) in human aortic SMCs (HASMCs) under the condition of calcifying medium containing 10 mM β-glycerophosphate (β-GP). The experiments showed that NaHS (an H2S donor, 100 μM) mitigated the calcification of HASMCs treated with high glucose by decreasing calcium and phosphorus levels, calcium deposition and ALP activity and inhibited osteogenic transformation by increasing SMα-actin and SM22α, two phenotypic markers of smooth muscle cells, and decreasing core binding factor α-1 (Cbfα-1), a key factor in bone formation, protein expressions in HASMCs. Moreover, NaHS administration inhibited the activation of Stat3, cathepsin S (CAS) activity and its expression, but increased the level of elastin protein. Pharmacological inhibition or gene silencing Stat3 not only reversed elastin loss, but also attenuated CAS expression. Inhibition of CAS alleviated, while CAS overexpression exacerbated, elastin loss. Interestingly, overexpression of wild type (WT)-Stat3, but not its mutant C259S, elevated CAS protein expression and reduced elastin level. Moreover, NaHS induced S-sulfhydration in WT, but not in the C259S Stat3. These data suggest that H2S may directly regulate Cys259 residue in Stat3 and then impair its signaling function. Our data indicate that H2S may attenuate vascular calcification by upregulating elastin level through the inhibition of Stat3/CAS signaling.

scholarly journals Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jun-Li Zhao ◽  
Ting Zhang ◽  
Xia Shao ◽  
Jun-Jun Zhu ◽  
Mei-Zi Guo
Keyword(s):  
Peritoneal Dialysis ◽  
Peritoneal Fluid ◽  
Transforming Growth Factor ◽  
Collagen I ◽  
Control Group ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Peritoneal Fibrosis ◽  
Jnk Pathway ◽  
Tgf Β1

Abstract Background Peritoneal fibrosis (PF) remains a serious complication of long-term peritoneal dialysis (PD). The goal of this study was to investigate the anti-fibrotic effects of curcumin on the PF response to PD and its’ mechanism. Methods Male Sprague–Dawley rats were infused with 20 mL of 4.25% glucose-based standard PD fluid for 8 consecutive weeks to establish PF model and then divided into five groups: Control, received sham operation and 0.9% physiological saline; PD, received 4.25% standard PD fluid; Curcumin, PD rats injected intraperitoeally with curcumin for 8 weeks at doses of 10, 20 or 40 mg/kg. Masson’s staining was performed to evaluate the extent of PF. Peritoneal Equilibration Test (PET) was conducted to assess ultrafiltration volume (UFV) and mass transfer of glucose (MTG), quantitative RT-PCR, and immunohistochemistry or western blotting were performed to measure the expression levels of inflammation and fibrosis-associated factors. We also detected the TGF-β1 in peritoneal fluid by ELISA. Results Compared with the control group, the PD rats showed decreased UFV (2.54 ± 0.48 to 9.87 ± 0.78 mL, p < 0.05] and increased MTG (18.99 ± 0.86 to 10.85 ± 0.65 mmol/kg, p < 0.05) as well as obvious fibroproliferative response, with markedly increased peritoneal thickness (178.33 ± 4.42 to 25.26 ± 0.32um, p < 0.05) and higher expression of a-SMA, collagen I and TGF-β1. Treatment with curcumin significantly increased UFV, reduced MTG and peritoneal thickness of PD rats. The elevated TGF-β1 in peritoneal fluid of PD rats was significantly decreased by curcumin. It attenuated the increase in protein and mRNA of TGF-β1, α-SMA and collagen I in peritoneum of PD rats. The mRNA expressions of TAK1, JNK and p38, as well as the protein expressions of p-TAK1, p-JNK and p-p38 in peritoneum of PD rats were reduced by curcumin. Conclusions Present results demonstrate that curcumin showed a protective effect on PD-related PF and suggest an implication of TAK1, p38 and JNK pathway in mediating the benefical effects of curcumin.

scholarly journals Knockdown of Angiopoietin-Like Protein 2 Ameliorates Diabetic Nephropathy by Inhibiting TLR4

2017 ◽  
Vol 43 (2) ◽  
pp. 685-696 ◽  
Author(s):  
Suxia Yang ◽  
Junwei Zhang ◽  
Shiying Wang ◽  
Jun Shi ◽  
Xinxin Zhao
Keyword(s):  
Diabetic Nephropathy ◽  
Western Blot ◽  
Inflammatory Cytokines ◽  
Renal Injury ◽  
Collagen Iv ◽  
Pcr Analysis ◽  
Control Group ◽  
Tlr4 Expression ◽  
Qrt Pcr ◽  
Tgf Β1

Background/Aims: Angiopoietin-like protein 2 (ANGPTL2) was reported to be implicated in the pathogenesis of inflammatory disease. Its role in diabetic nephropathy (DN) remained illdefined. Methods: qRT-PCR and western blot analysis were performed to detect the expressions of ANGPTL2 or TLR4 in streptozotocin (STZ)-induced DN rats and HG-stimulated podocytes. The renal injury index including 24-h proteinuria, blood glucose level, serum creatinine and blood urea nitrogen were measured in DN rats using corresponding commercial kits. The effect of ANGPTL2 knockdown on the secretion or expression of inflammatory cytokines was detected by ELISA or qRT-PCR analysis. The effect of ANGPTL2 knockdown on extracellular matrix (ECM) accumulation was determined by testing TGF-β1, Collagen-IV, fibronectin (FN) and PTEN expression via western blot. Results: ANGPTL2 and TLR4 were both highly expressed in DN rats compared with control group. ANGPTL2 knockdown alleviated renal injury in STZ-induced DN rat model. ANGPTL2 knockdown also suppressed inflammatory cytokines (IL-6, TNF-α, MCP-1, IL-1β) expression and ECM accumulation (TGF-β1, Collagen-IV, FN, PTEN) in HG-induced podocytes. Moreover, ANGPTL2 knockdown led to a significant decrease of TLR4 expression in both DN rat and cell model. Furthermore, TAK-242 treatment exacerbated the inhibitory effect of ANGPTL2 knockdown on inflammatory cytokines expression and ECM accumulation in HG-induced podocytes. Conclusion: ANGPTL2 knockdown ameliorates DN by inhibiting TLR4 expression, an observation contributing to a better understanding of DN pathogenesis.

Triptolide Improves Renal Injury in Diabetic Nephropathy Rats through TGF-β1/Smads Signal Pathway

2020 ◽  
Vol 20 ◽  
Author(s):  
Ruoyu Pang ◽  
Donghai Gu
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Diabetic Rats ◽  
Control Group ◽  
Inflammatory Factor ◽  
Group Model ◽  
Model Group ◽  
Tnf Α ◽  
Smad7 Expression ◽  
Tgf Β1

Objective: To investigate the therapeutic effect and mechanism of Triptolide on renal injury in diabetic nephropathy rats. Methods: A total of 15 male SD rats aged 8 weeks were randomly divided into five groups (3 rats in each group): control group, model group, Triptolide low-dose (Triptolide-L) group, Triptolide medium-dose (Triptolide-M) group, Triptolide high-dose (Triptolide-H) group. The rats models of diabetic nephropathy (DN) were established by a single intraperitoneal injection of STZ after being fed with high-fat and high-sugar diet for 4 weeks, and the fasting blood glucose (FBG) concentration of rats was detected. After 4 weeks, HE-staining was used to evaluate the renal pathological damage in rats; biochemical analysis was used to determine the blood urea nitrogen (BUN), serum creatinine (SCr), total cholesterol (TC), triglyceride (TG); ELISA was used to measure the serum inflammatory factor levels; Western blot (WB) was used to detect the expression of TGF-β1/Smads pathway proteins. Results: In the four FBG tests (once a week), the FBG concentration in the model group was significantly higher than that in the control group, while Triptolide-treated rats were significantly lower than that in the model group. Rats in Model group showed obvious renal injury, and Triptolide significantly improved the renal injury in DN rats. Compared with the control group, the expression of BUN, SCr, TC, TG, inflammatory factors TNF-α, IL-6 and IL-1β in the model group increased significantly. WB results showed that the expressions of TGF-β1, Smad3, α-SMA and vimentin in the kidney significantly increased, while the Smad7 expression significantly decreased. Triptolide significantly reduced the levels of BUN, SCr, TC, TG and TNF-α, IL-6, IL-1β in diabetic rats, decreased the expression of TGF-β1, Smad3, α-SMA, vimentin, and increased the Smad7 expression. In different doses of Triptolide treatment group, its effect showed a significant concentration dependence. Conclusion: Triptolide alleviates renal injury in diabetic rats by inhibiting the TGF-β1/Smads signaling pathway.

Mechanism and Treatment of Sulfide-Induced Coma: A Rat Model

2008 ◽  
Vol 27 (3) ◽  
pp. 287-293 ◽  
Author(s):  
A. F. Almeida ◽  
P. N. Nation ◽  
T. L. Guidotti
Keyword(s):  
Hydrogen Sulfide ◽  
Rat Model ◽  
Sprague Dawley ◽  
Sodium Hydrosulfide ◽  
Sprague Dawley Rats

Sodium hydrosulfide and dimethylsulfide duplicate the effects of hydrogen sulfide in causing coma in Sprague-Dawley rats and are additive for lethality. Nitrite, pyruvate and dithiothreitol had no significant effect on coma or lethality but bicarbonate with and without glucose reduced duration of coma. This finding suggests an antidotal treatment.

scholarly journals Nephroprotective effect of losartan in IgA model rat

2019 ◽  
Vol 47 (10) ◽  
pp. 5205-5215
Author(s):  
Li Xing ◽  
Er Lin Song ◽  
Xi Bei Jia ◽  
Jing Ma ◽  
Bing Li ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
Control Group ◽  
Model Group ◽  
Sprague Dawley ◽  
Tubulointerstitial Injury ◽  
Expression Levels ◽  
Losartan Group ◽  
Tgf Β1

Objective This study was performed to investigate the possible nephroprotective effects of losartan in a rat model of experimental IgA nephropathy (IgAN). Methods Thirty male Sprague–Dawley rats were randomly divided into three groups. The rats in the model group were treated with bovine serum albumin (oral gavage), lipopolysaccharide (tail vein injection), and carbon tetrachloride (subcutaneous injection); rats in the losartan group received treatments similar to those of the model group, and were orally gavaged with losartan; and rats in the control group received phosphate-buffered saline alone (both orally and intravenously). Results Losartan treatment lowered the 24-hour urinary protein, serum blood urea nitrogen, and serum creatinine levels. Proliferating mesangial cells with a variable increase in the mesangial matrix were detected in the model group, whereas injury in the losartan group was significantly attenuated. Immunohistochemistry revealed that the expression levels of transforming growth factor (TGF)-β1 and α-smooth muscle actin were significantly elevated in the model group but reduced in the losartan group. The expression levels of TGF-β1 and monocyte chemoattractant protein-1 were minimal in the control group, significantly increased in the model group, and reduced in the losartan group. Conclusion Losartan has a protective effect against tubulointerstitial injury in IgAN.

scholarly journals Expression of Transforming Growth Factor Beta Isoforms in Canine Endometrium with Cystic Endometrial Hyperplasia–Pyometra Complex

Animals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1844
Author(s):  
Marta Rybska ◽  
Magdalena Woźna-Wysocka ◽  
Barbara Wąsowska ◽  
Marek Skrzypski ◽  
Magdalena Kubiak ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Endometrial Hyperplasia ◽  
Transforming Growth Factor ◽  
Control Group ◽  
Key Factor ◽  
Growth Factor Beta ◽  
Uterine Diseases ◽  
Tgf Β1

Cystic endometrial hyperplasia (CEH) and pyometra are the most frequently diagnosed uterine diseases affecting bitches of different ages. Transforming growth factor beta (TGF-β) has been classified in females as a potential regulator of many endometrial changes during the estrous cycle or may be involved in pathological disorders. The aim of this study was to determine the expression of TGF-β1, -β2 and -β3 in the endometrium of bitches suffering from CEH or a CEH–pyometra complex compared to clinically healthy females (control group; CG). A significantly increased level of TGF-β1 mRNA expression was observed in the endometrium with CEH–pyometra compared to CEH and CG. Protein production of TGF-β1 was identified only in the endometrium of bitches with CEH–pyometra. An increase in TGF-β3 mRNA expression was observed in all the studied groups compared to CG. The expression of TGF-β2 mRNA was significantly higher in CEH and lower in CEH–pyometra uteri. The results indicate the presence of TGF-β cytokines in canine endometrial tissues affected by proliferative and degenerative changes. However, among all TGF-β isoforms, TGF-β1 could potentially be a key factor involved in the regulation of the endometrium in bitches with CEH–pyometra complex.

scholarly journals Yiqi Jiedu Huayu Decoction Alleviates Renal Injury in Rats With Diabetic Nephropathy by Promoting Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Chen Xuan ◽  
Yu-Meng Xi ◽  
Yu-Di Zhang ◽  
Chun-He Tao ◽  
Lan-Yue Zhang ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Mtor Pathway ◽  
Control Group ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Periodic Acid Schiff

Diabetic nephropathy (DN), a common microvascular complication of diabetes, is one of the main causes of end-stage renal failure (ESRD) and imposes a heavy medical burden on the world. Yiqi Jiedu Huayu decoction (YJHD) is a traditional Chinese medicine formula, which has been widely used in the treatment of DN and has achieved stable and reliable therapeutic effects. However, the mechanism of YJHD in the treatment of DN remains unclear. This study aimed to investigate the mechanism of YJHD in the treatment of DN. Sprague-Dawley rats were randomly divided into a normal control group, a diabetic group, an irbesartan group, and three groups receiving different doses of YJHD. Animal models were constructed using streptozotocin and then treated with YJHD for 12 consecutive weeks. Blood and urine samples were collected during this period, and metabolic and renal function was assessed. Pathological kidney injury was evaluated according to the kidney appearance, hematoxylin-eosin staining, Masson staining, periodic-acid Schiff staining, periodic-acid Schiff methenamine staining, and transmission electron microscopy. The expression levels of proteins and genes were detected by immunohistochemistry, western blotting, and real-time qPCR. Our results indicate that YJHD can effectively improve renal function and alleviate renal pathological injury, including mesangial matrix hyperplasia, basement membrane thickening, and fibrosis. In addition, YJHD exhibited podocyte protection by alleviating podocyte depletion and morphological damage, which may be key in improving renal function and reducing renal fibrosis. Further study revealed that YJHD upregulated the expression of the autophagy-related proteins LC3II and Beclin-1 while downregulating p62 expression, suggesting that YJHD can promote autophagy. In addition, we evaluated the activity of the mTOR pathway, the major signaling pathway regulating the level of autophagy, and the upstream PI3K/Akt and AMPK pathways. YJHD activated the AMPK pathway while inhibiting the PI3K/Akt and mTOR pathways, which may be crucial to its promotion of autophagy. In conclusion, our study shows that YJHD further inhibits the mTOR pathway and promotes autophagy by regulating the activity of the PI3K/Akt and AMPK pathways, thereby improving podocyte injury, protecting renal function, and reducing renal fibrosis. This study provides support for the application of and further research into YJHD.

scholarly journals Dendrobium Mixture Improved Diabetic Nephropathy in db/db Mice by Regulating TGF-β1/Smads Signal Transduction

2021 ◽  
Author(s):  
Yong Chen ◽  
Xiaohui Lin ◽  
Yanfang Zheng ◽  
Wenzhen Yu ◽  
Fan Lin ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Diabetic Nephropathy ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Fasting Blood Glucose ◽  
Blood Lipid ◽  
Control Group ◽  
Tgf Β1

Abstract BackgroundDendrobium mixture (DMix) is an effective treatment for diabetic nephropathy (DN), but the underlying molecular mechanism remains unclear. In this study, we investigated whether DMix regulates the transforming growth factor-β1 (TGF-β1)/Smads signal transduction pathway. MethodsTwenty-four db/db mice were randomly divided into three groups: the model, DMix, and gliquidone groups, while eight db/m mice were selected as the normal control group. The drug was administered by continuous gavage for 8 weeks. Body weight (BW), kidney weight (KW), kidney index, fasting blood glucose (FBG), blood lipid, 24-hour urinary albumin excretion rate, blood urea nitrogen, and serum creatinine levels were measured. Pathological changes in the renal tissue were observed using a light microscope. Real-time quantitative PCR and immunohistochemical staining were used to detect mRNA expression of TGF-β1 and alpha-smooth muscle actin (α-SMA) genes and proteins, respectively, in renal tissues. TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3, and α-SMA expression levels were measured using western blotting. ResultsDMix significantly reduced FBG level, BW, KW, and blood lipid level, and improved renal function in db/db mice. Histopathology showed that DMix alleviated glomerular mesangial cell proliferation and renal interstitial fibrosis in db/db mice. Additionally, DMix reduced protein and mRNA expression of TGF-β1 and α-SMA, and inhibited Smad2 and Smad3 phosphorylation. ConclusionsThe findings suggest that DMix may inhibit renal fibrosis and delay the progression of DN by regulating the TGF-β1/Smads signaling pathway. Key words: Diabetic nephropathy, Dendrobium mixture, TGF-β1/Smads signaling pathway

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