Effects of Qingshen granules on Janus Kinase/signal transducer and activator of transcription signaling pathway in rats with unilateral ureteral obstruction
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摘要
OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the medium dose QSG-treated group.CONCLUSION: Our data suggest that the leptin-mediated JAK/STAT signaling pathway is involved in the process of renal interstitial fibrosis in UUO rats. QSG inhibited the activity of the signaling pathway, reduced the activity of NF-k B and inflammatory effect, and the transdifferentiation in the renal tubular epithelial cells. Treatment with QSG may delay the renal fibrosis and protect the renal function from damage following UUO in rats.
OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the medium dose QSG-treated group.CONCLUSION: Our data suggest that the leptin-mediated JAK/STAT signaling pathway is involved in the process of renal interstitial fibrosis in UUO rats. QSG inhibited the activity of the signaling pathway, reduced the activity of NF-k B and inflammatory effect, and the transdifferentiation in the renal tubular epithelial cells. Treatment with QSG may delay the renal fibrosis and protect the renal function from damage following UUO in rats.
OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the medium dose QSG-treated group.CONCLUSION: Our data suggest that the leptin-mediated JAK/STAT signaling pathway is involved in the process of renal interstitial fibrosis in UUO rats. QSG inhibited the activity of the signaling pathway, reduced the activity of NF-k B and inflammatory effect, and the transdifferentiation in the renal tubular epithelial cells. Treatment with QSG may delay the renal fibrosis and protect the renal function from damage following UUO in rats.
引文
[1] Lovisa S,Zeisberg M,Kalluri R.Partial epithelial-to-mesenchymal transition and other new mechanisms of kidney fibrosis.Trends Endocrinol Metab 2016;27(10):681-695.
2 Wang YP,Li WJ,Cao EZ,et al.Effects of Qingshen decoction on serum leptin and interleukin-6 in patients with chronic renal failure and acute exacerbation of damp heat syndrome.Zhong Guo Zhong Xi Jie He Ji Jiu Za Zhi2005;12(2):71-75.
3 Ibars M,Ardid-Ruiz A,Suárez M,Muguerza B,BladéC,Aragonès G.Proanthocyanidins potentiate hypothalamic leptin/STAT3 signalling and Pomc gene expression in rats with diet-induced obesity.Int J Obes(Lond)2016;18(10):1-8.
4 Koike K,Ueda S,Yamagishi S,et al.Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction.Clin Immunol 2014;150(1):78-87.
5 Chuang PY,He JC.JAK/STAT signaling in renal diseases.Kidney Int 2010;78(3):231-234.
6 Chen Q.Research methodology of pharmacology of Traditional Chinese Medicine.3 rd ed.Beijing:People's Medical Publishing House,2011:412-413.
7 Yaylali A,Ergin K,Ce?en S.Effect of resveratrol on leptin and sirtuin 2 expression in the kidneys in streptozotocin-induced diabetic rats.Anal Quant Cytopathol Histpathol 2015;37(4):243-251.
8 Louren?o EV,Liu A,Matarese G,La Cava A.Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation.Proc Natl Acad Sci USA 2016;113(38):10637-10642.
9 Shin HJ,Oh J,Kang SM.Leptin induces hypertrophy via p38 mitogen-activated protein kinase in rat vascular smooth muscle cells.Biochem Biophys Res Commun2005;329(1):18-24.
10 Rajapurohitam V,Can XT,Kirshenbaum LA.The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes.Circ Res 2003;93:277-279.
11 Rachakonda V,Borhani AA,Dunn MA,Andrzejewski M,Martin K,Behari J.Serum leptin is a biomarker of malnutrition in decompensated cirrhosis.PLo S One 2016;11(9):159-175.
12 Kümpers P,Gueler F,Rong S,Mengel M,Tossidou I,Peters I.Leptin is a coactivator of TGF-beta in unilateral ureteral obstructive kidney disease.Am J Physiol Renal Physiol 2007;293(4):F1355-F1362.
13 Wolf G,Hamann A,Han DC,et al.Leptin stimulates proliferation and TGF-beta expression in renal glomemlar endothelial cells:potential role in glomemlosclerosis.Kidney Int l999;56(3):860-872.
14 Schaab M,Kratzsch J.The soluble leptin receptor.Best Pract Res Clin Endocrinol Metab 2015;29(5):661-670.
15 Mullen M,Gonzalez-Perez RR.Leptin-induced JAK/STAt signaling and cancer growth.Vaccines(Basel)2016;4 (3):E26.
16 Villarino AV,Kanno Y,Ferdinand JR,O'Shea JJ.Mechanisms of Jak/STAT signaling in immunity and disease.J Immunol 2015;194(1):21-27.
17 Mao T,Chen H,Hong L,Li J.Pigment epithelium-derived factor inhibits high glucose-induced JAK/STAT signalling pathway activation in human glomerular mesangial cells.Saudi Med J 2013;34(8):793-800.
18 Huang F,Xiong X,Wang H,You S,Zeng H.Leptin-induced vascular smooth muscle cell proliferation via regulating cell cycle,activating ERK1/2 and NF-kappa B.Acta Biochim Biophys Sin(Shanghai)2010;42(5):325-331.
19 Lou L,Liu Y,Zhou J,et al.Chlorogenic acid and luteolin synergistically inhibit the proliferation of interleukin-1β-induced fibroblast-like synoviocytes through regulating the activation of NF-κB and JAK/STAT-signaling pathways.Immunopharmacol Immunotoxicol 2015;37(6):499-507.
2 Wang YP,Li WJ,Cao EZ,et al.Effects of Qingshen decoction on serum leptin and interleukin-6 in patients with chronic renal failure and acute exacerbation of damp heat syndrome.Zhong Guo Zhong Xi Jie He Ji Jiu Za Zhi2005;12(2):71-75.
3 Ibars M,Ardid-Ruiz A,Suárez M,Muguerza B,BladéC,Aragonès G.Proanthocyanidins potentiate hypothalamic leptin/STAT3 signalling and Pomc gene expression in rats with diet-induced obesity.Int J Obes(Lond)2016;18(10):1-8.
4 Koike K,Ueda S,Yamagishi S,et al.Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction.Clin Immunol 2014;150(1):78-87.
5 Chuang PY,He JC.JAK/STAT signaling in renal diseases.Kidney Int 2010;78(3):231-234.
6 Chen Q.Research methodology of pharmacology of Traditional Chinese Medicine.3 rd ed.Beijing:People's Medical Publishing House,2011:412-413.
7 Yaylali A,Ergin K,Ce?en S.Effect of resveratrol on leptin and sirtuin 2 expression in the kidneys in streptozotocin-induced diabetic rats.Anal Quant Cytopathol Histpathol 2015;37(4):243-251.
8 Louren?o EV,Liu A,Matarese G,La Cava A.Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation.Proc Natl Acad Sci USA 2016;113(38):10637-10642.
9 Shin HJ,Oh J,Kang SM.Leptin induces hypertrophy via p38 mitogen-activated protein kinase in rat vascular smooth muscle cells.Biochem Biophys Res Commun2005;329(1):18-24.
10 Rajapurohitam V,Can XT,Kirshenbaum LA.The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes.Circ Res 2003;93:277-279.
11 Rachakonda V,Borhani AA,Dunn MA,Andrzejewski M,Martin K,Behari J.Serum leptin is a biomarker of malnutrition in decompensated cirrhosis.PLo S One 2016;11(9):159-175.
12 Kümpers P,Gueler F,Rong S,Mengel M,Tossidou I,Peters I.Leptin is a coactivator of TGF-beta in unilateral ureteral obstructive kidney disease.Am J Physiol Renal Physiol 2007;293(4):F1355-F1362.
13 Wolf G,Hamann A,Han DC,et al.Leptin stimulates proliferation and TGF-beta expression in renal glomemlar endothelial cells:potential role in glomemlosclerosis.Kidney Int l999;56(3):860-872.
14 Schaab M,Kratzsch J.The soluble leptin receptor.Best Pract Res Clin Endocrinol Metab 2015;29(5):661-670.
15 Mullen M,Gonzalez-Perez RR.Leptin-induced JAK/STAt signaling and cancer growth.Vaccines(Basel)2016;4 (3):E26.
16 Villarino AV,Kanno Y,Ferdinand JR,O'Shea JJ.Mechanisms of Jak/STAT signaling in immunity and disease.J Immunol 2015;194(1):21-27.
17 Mao T,Chen H,Hong L,Li J.Pigment epithelium-derived factor inhibits high glucose-induced JAK/STAT signalling pathway activation in human glomerular mesangial cells.Saudi Med J 2013;34(8):793-800.
18 Huang F,Xiong X,Wang H,You S,Zeng H.Leptin-induced vascular smooth muscle cell proliferation via regulating cell cycle,activating ERK1/2 and NF-kappa B.Acta Biochim Biophys Sin(Shanghai)2010;42(5):325-331.
19 Lou L,Liu Y,Zhou J,et al.Chlorogenic acid and luteolin synergistically inhibit the proliferation of interleukin-1β-induced fibroblast-like synoviocytes through regulating the activation of NF-κB and JAK/STAT-signaling pathways.Immunopharmacol Immunotoxicol 2015;37(6):499-507.