Involvement of hydrogen sulfide in the progression of renal fibrosis / 中华医学杂志(英文版)

OBJECTIVE@#Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application.@*DATA SOURCES@#Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels."@*STUDY SELECTION@#Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files.@*RESULTS@#The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis.@*CONCLUSIONS@#We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.

Impact of rosuvastatin on atherosclerosis lesions in apolipoprotein E knockout mice / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effect of rosuvastatin on atherosclerosis in apoE-knockout (apoE-/-) mice.</p><p><b>METHODS</b>Eighteen 6-week-old apoE-/- mice fed with high fat diet were used as atherosclerosis models, twelve 6-week-old C57BL/6 mice fed with normal diet were used as control. After twelve weeks, six apoE-/- mice were used to observe the formation of atherosclerosis. Another 12 apoE-/- mice were divided into placebo treated group (n = 6) and rosuvastatin group (n = 6, 10 mg×kg(-1)×d(-1) per gavage) and treated for 12 weeks. Then, blood was collected for measuring lipid, aorta was prepared for morphologic study (HE, Oil red O, Masson) and immunohistochemical analysis (α-smooth active protein, transforming growth factor β(1), macrophage surface molecule-3).</p><p><b>RESULTS</b>Serum cholesterol and low density lipoprotein levels were significantly higher in apoE-/- mice fed with high fat diet than in C57/BL6 mice(all P < 0.01)while triglyceride level was similar between the two groups, these were not affected by rosuvastatin. Similarly, atherosclerotic lesion area in apoE-/- mice fed with high fat diet was also not significantly reduced by rosuvastatin, while lipid deposition could be significantly reduced and collagen deposition could be significantly increased in the aortic atherosclerotic lesions by treatment with rosuvastatin. Upregulated TGF-β(1) and Mac-3 expression in the aortic atherosclerotic lesions in apoE-/- mice fed with high fat diet could also be significantly reduced by rosuvastatin (all P < 0.01), suggesting reduce inflammatory responses in the atherosclerotic lesion and stable atherosclerotic plaque post rosuvastatin treatment.</p><p><b>CONCLUSION</b>Reducing inflammatory responses and stabilizing plaque properties might contribute to the anti-atherosclerosis effects of rosuvastatin in mice high fat diet fed apoE-/- mice.</p>

The effect of losartan on glomerular sclerosis in rats with diabetic nephropathy / 中南大学学报(医学版)

OBJECTIVE@#To explore the degradation mechanism of losartan on extracellular matrix in rats with diabetic nephropathy.@*METHODS@#The rat model of diabetic nephropathy was established by streptozotozin(STZ) injection, and the rats were randomly divided into 3 groups: (a normal group, a model group and a losartan group). For 16 weeks, the serum creatinine and urea nitrogen were measured, and glomerular sclerosis index(GSI) were caculated. The expression of collagen Type IV,connective tissue growth factor and transforming growth factor-beta1 were examined by Western blot and real time-PCR respectively.@*RESULTS@#Blood urea nitrogen, GSI and the expressions of collagen Type IV and CTGF protein in the losartan group were lower than those in the model group(all P<0.05), and the expressions of collagen Type IV mRNA,TGF-beta1 mRNA and CTGF mRNA were lower than those in the model group (all P<0.05).@*CONCLUSION@#Losartan modulates glomerular sclerosis and decreases the accumulation of collagen Type IV by inhibiting TGF-beta1 and CTGF.

Effect of enalapil on renal interstitial fibrosis in rats with unilateral ureteral obstruction / 中南大学学报(医学版)

OBJECTIVE@#To investigate the effect of enalapril on renal interstitial fibrosis in rats with unilateral ureteral obstruction(UUO).@*METHODS@#UUO model was induced by ligating the left ureter in rats. Male Sprague-Dawley(SD) rats were randomly divided into a sham-operated group(n=16), a UUO model group(n=24), and an enalapril treated group(n=24). The rats were treated with 10 mg/kg.d by gastric gavage in the enalapril treated group from 24 h before the operation, and the rats were treated with the identical dose of normal saline in the other 2 groups. The rats were sacrificed at 3,7,14, and 21 days after UUO. Pathological changes of the renal tissue were observed by HE and Masson staining, the mRNA expression of collagen I (Col I) was detected by real-time PCR, and the protein expression of connective tissue growth factor (CTGF) was detected by Western blot.@*RESULTS@#The renal interstitial damage index, relative collagen area and the expression of Col I mRNA and CTGF in the renal tissues in the model group increased with the prolongation of obstruction. Enalapril significantly reduced the renal interstitial damage index and relative collagen area, and inhibted the expression of Col I mRNA and CTGF. There was significant difference on day 3,7,and 14 (P0.05).@*CONCLUSION@#Enalapril significantly attenuates renal interstitial fibrosis by supressing the expression of Col I mRNA and CTGF.

Effect of losartan on the expressions of TGF-beta1, p-Smad2/3, and Smad7 in the remnant renal tissues of 5/6 nephrectomized rats / 中南大学学报(医学版)

OBJECTIVE@#To investigate the mechanism of losartan treating glomerulosclerosis and to observe the effect of losartan on the expressions of TGF-beta1, p-Smad2/3, and Smad7 in the renal tissues of 5/6 nephrectomized rats.@*METHODS@#Male Wistar rats were randomly divided into a sham-operated group, a 5/6 nephrectomized model group, and a losartan treated group. The rats in the model group and the losartan treated group were performed 5/6 nephrectomy by the method with 2 procedures. Twelve weeks after of the operation, all rats were killed. The 24-hour urinary protein, serum creatinine, and urea nitrogen were detected. Pathological changes of the renal tissues were observed by HE and Masson staining, and the expressions of TGF-beta1, p-Smad2/3, and Smad7 were detected by immunohistochemical staining.@*RESULTS@#The 24-hour urinary protein, serum creatinine, urea nitrogen, and the relative area of collagen in the renal tissues of the rats in the model group significantly increased (P<0.01), and losartan could reduce these indexes. The expressions of TGF-beta1 and p-Smad2/3 were just at a low level in the renal tissues of the rats in the sham-operated group, and were strongly positive in the model group; but losartan could decrease the expressions of TGF-beta1 and p-Smad2/3 (P<0.01). The expression of Smad7 in the model group was fewer than that in the sham-operated group (P<0.01), but losartan could improve the expression of Smad7 (P<0.01).@*CONCLUSION@#Losartan may implement its anti-glomerulosclerosis by affecting TGF-beta1, p-Smad2/3, and Smad7 of TGF-beta/Smads pathway of the renal tissues of 5/6 nephrectomized rats.

Level of asymmetric dimethylarginine and carotid atherosclerosis in patients with chronic kidney disease / 中南大学学报(医学版)

OBJECTIVE@#To determine the association between asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, with atherosclerosis in patients with chronic kidney disease (CKD).@*METHODS@#One hundred thirty-eight CKD patients were enrolled in this study. Serum levels of L-arginine, ADMA, and SDMA were measured by high-performance liquid chromatography (HPLC). Common carotid arteries intimae-medial thickness (CCA-IMT), cross-sectional calculated intimae-medial thickness (cIM area) and atherosclerotic plaque were detected by noninvasive high-resolution B-mode ultrasonography.@*RESULTS@#Serum levels of ADMA and SDMA were significantly increased in CKD patients (n=138) compared with age matched healthy subjects (n=42, P<0.01). ADMA and SDMA levels increased with the progression of renal dysfunction and were negatively related to creatinine clearance (Ccr) in pre-dialysis patients (r=-0.315, P<0.05; r=-0.426, P<0.01). Serum levels of ADMA and SDMA in dialysis patients (n=74) were significantly higher than those in pre-dialysis patients (P<0.05). Patients with carotid artery plaques showed significantly higher levels of ADMA compared with those without plaques. Serum levels of ADMA closely correlated with the mean IMT (r=0.471, P<0.01) and cIM area value (r=0.430, P<0.01). These correlations remained significant even after adjusting GFR, age, gender ,and other risk factors for atherosclerosis in the multiple regression analysis.@*CONCLUSION@#Serum levels of ADMA increased with the progression of CKD and may play a role in the pathogenesis of accelerated atherosclerosis in CKD patients.

P21 expression in renal interstitial fibrosis and regulative effect of enalapril / 中南大学学报(医学版)

OBJECTIVE@#To investigate the expression of P21 in renal interstitial fibrosis rats and the effect of enalapril on it.@*METHODS@#Sprague Dawley rats were randomly divided into 3 groups: a sham operation group,a unilateral urethral obstruction group, and an enalapril treatment group. The expression of P21 in renal tubular epithelial cells on the process was detected by immunohistochemistry at different time spots (7, 14, 21 d after UUO, sham-surgery or enalapril treatment). The expression of p21 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR).@*RESULTS@#Seven days after the surgery, significant differences were found in P21 expression between UUO and SOR renal tubular cells. With degree of interstitial fibrosis aggravating, P21 expression increased. Enalapril can inhibit its expression.@*CONCLUSION@#In the kidney of UUO rats, P21 expression increased and enalapril possessed significant inhibitory effects on the procedure. P21 may participate in the pathogenesis of renal tubule-interstitial fibrosis.

Expression of p27 in rat kidney with unilateral ureteral obstruction and the therapeutic effect of enalapril / 中南大学学报(医学版)

OBJECTIVE@#To explore the effect of p27 in the renal tubule on the process of renal interstitial fibrosis caused by unilateral ureteral obstruction (UUO) in rats, and to examine the expression changes of p27 after enalapril intervention and to interpret the anti-fibrotic mechanism.@*METHODS@#Ninety rats were randomly divided into the sham-operated group (SOR), UUO group,and UUO+enalapril treatment group [enalapril: 10 mg/(kg.d)]. The rats of each group were respectively sacrificed on 7, 14, 21 days post-operatively. The renal pathological changes were dynamically observed by HE. The expression and dynamic changes of p27 were detected by immunohistochemistry. The level of p27 mRNA were detected by RT-PCR.@*RESULTS@#The expression of p27 in renal tubular epithelial cells and p27 mRNA were strongly positive in the SOR group. With degree of interstitial fibrosis aggravating, the expression of p27 mRNA was gradually reducing. Enalapril could improve the expression of p27 on the 14th and 21st days after the UUO.@*CONCLUSION@#(1) This study supports a causative role of p27 in the formation of fibrosis of renal mesenchyme in rats with UUO. (2) The anti-fibrotic mechanism of enalapril is partly the improvement of p27 expression.

Changes of serum asymmetric dimethylarginine in essential hypertension before and after the treatment / 中南大学学报(医学版)

OBJECTIVE@#To investigate the relationship between serum asymmetric dimethylarginine (ADMA) and blood pressure as well as target organ damage in essential hypertension, and to evaluate the effects of enalapril and losartan on them.@*METHODS@#Forty-two newly diagnoszed patients with essential hypertension were randomly divided into enalapril-treated group and losartan-treated group. Serum ADMA, L-arginine, and nitric oxide( NO) were measured before and after the treatment for 8 weeks. Twenty-three healthy volunteers were included as control subjects.@*RESULTS@#The concentrations of ADMA and L-arginine in serum were significantly higher but the level of nitric oxide was relatively lower ( P < 0.01 ) in hypertensive patients than those in control subjects. Serum ADMA was higher in different levels of blood pressure and target organ damage. Treatment with enalapril or losartan for 8 weeks not only reduced blood pressure but also decreased serum ADMA (P <0.01 ). Furthermore, treatment with these drugs also increased the level of serum nitric oxide but didn't change the level of L-arginine.@*CONCLUSION@#The concentrations of serum ADMA and L-arginine were increased, but the level of nitric oxide was decreased in the early stage of essential hypertension. Both enalapril and losartan could ameliorate the endothelial function by reducing the concentration of ADMA.