Verbascoside alleviates renal fibrosis in unilateral ureteral obstruction rats by inhibiting macrophage infiltration

Document Type : Original Article

Authors

1 Guizhou University School of Medicine, Guizhou University, Gui Yang, Gui Zhou, China

2 The NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Gui Yang, Gui Zhou, China

3 Department of Nephrology, Guizhou Provincial People’s Hospital, Gui Yang, Gui Zhou, China

4 Department of Thoracic Surgery, Guizhou Provincial People’s Hospital, Gui Yang, Gui Zhou, China

Abstract

Objective(s): To explore the effect of verbascoside on renal fibrosis in unilateral ureteral obstruction (UUO) rats.
Materials and Methods: Twenty Sprague-Dawley rats were randomly distributed into sham-operated, UUO, and UUO+Verbascoside groups. After two weeks of rat model construction, urine and blood samples were collected for biochemical analysis while kidney tissues were harvested for hematoxylin and eosin (H&E), Masson’s Trichrome, and immunohistochemistry staining. Pearson coefficient was used to analyze the correlation between the two proteins.
Results: Verbascoside improved UUO-induced renal dysfunction as detected by decreased serum creatinine, urea nitrogen, and urinary protein excretion rate. In UUO rats, H&E staining result revealed increased total nucleated cell number, and Masson’s Trichrome staining results showed tubular interstitial fibrosis with the deposition of collagen fibrils. Besides, expressions of fibrosis-related proteins including collagen type I (COL-I), α-smooth muscle actin (a-SMA), and tissue inhibitor of metalloproteinase 2 (TIMP2) expressed higher in the UUO group. Moreover, macrophage infiltration-related factors such as CD68+, F4/80+ cells, and suppressor of cytokine signaling-3 (SOCS3) were significantly higher in the UUO group than in sham-operated rats. However, after administration with verbascoside, the accumulation of collagen fibrils and total nucleated cell numbers were mitigated. Likewise, macrophage infiltration was extenuated and fibrosis-related proteins were down-regulated in the UUO+Verbascoside rats. Correlation analysis indicated that macrophage infiltration-related markers were related to fibrosis-related factors.
Conclusion: Verbascoside could alleviate renal fibrosis in UUO rats probably through ameliorating macrophage infiltration.

Keywords


1. Zhang ZH, He JQ, Qin WW, Zhao YY, Tan NH. Biomarkers of obstructive nephropathy using a metabolomics approach in rat. Chem Biol Interact 2018; 296:229-239.
2. Cai K, Chai L, Luo Q, Dai Z, Wu L, Hong Y. Full age spectrum equation versus CKD-EPI and MDRD equations to estimate glomerular filtration rate in adults with obstructive nephropathy. J Int Med Res 2019; 47:2394-2403.
3. Martínez-Klimova E, Aparicio-Trejo OE, Tapia E, Pedraza-Chaverri J. Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments. Biomolecules 2019; 9:141.
4. You YK, Luo Q, Wu WF, Zhang JJ, Zhu HJ, Lao L, et al. Petchiether A attenuates obstructive nephropathy by suppressing TGF-beta/Smad3 and NF-kappaB signalling. J Cell Mol Med 2019; 23:5576-5587.
5. Zeng G, Mai Z, Xia S, Wang Z, Zhang K, Wang L, et al. Prevalence of kidney stones in China: An ultrasonography based cross-sectional study. BJU Int 2017; 120:109-116.
6. Wu J, Yang Z, Wei J, Zeng C, Wang Y, Yang T. Association between serum magnesium and the prevalence of kidney stones: a cross-sectional study. Biol Trace Elem Res 2020; 195:20-26.
7. Yang C, Wang H, Zhao X, Matsushita K, Coresh J, Zhang L, et al. CKD in China: Evolving spectrum and public health implications. Am J Kidney Dis 2020; 76:258-264.
8. Stevens S. Obstructive Kidney Disease. Nurs Clin North Am 2018; 53:569-578.
9. Waasdorp M, Rooij DM, Florquin S, Duitman J, Spek CA. Protease-activated receptor-1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy. J Cell Mol Med 2019; 23:1268-1279.
10. Zhao J, Meng M, Zhang J, Li L, Zhu X, Zhang L, et al. Astaxanthin ameliorates renal interstitial fibrosis and peritubular capillary rarefaction in unilateral ureteral obstruction. Mol Med Rep 2019; 19:3168-3178.
11. Xianyuan L, Wei Z, Yaqian D, Dan Z, Xueli T, Zhanglu D, et al. Anti-renal fibrosis effect of asperulosidic acid via TGF-β1/smad2/smad3 and NF-κB signaling pathways in a rat model of unilateral ureteral obstruction. Phytomedicine 2019; 53:274-285.
12. Yang L, Yuan H, Yu Y, Yu N, Ling L, Niu J, et al. Epidermal growth factor receptor mimotope alleviates renal fibrosis in murine unilateral ureteral obstruction model. Clin Immunol 2019; 205:57-64.
13. Kamata M, Amano H, Ito Y, Fujita T, Otaka F, Hosono K, et al. Role of the high-affinity leukotriene B4 receptor signaling in fibrosis after unilateral ureteral obstruction in mice. PloS one 2019; 14:e0202842.
14. Han H, Zhu J, Wang Y, Zhu Z, Chen Y, Lu L, et al. Renal recruitment of B lymphocytes exacerbates tubulointerstitial fibrosis by promoting monocyte mobilization and infiltration after unilateral ureteral obstruction. J Pathol 2017; 241:80-90.
15. Ma W, Tao L, Wang X, Liu Q, Zhang W, Li Q, et al. Sorafenib inhibits renal fibrosis induced by unilateral ureteral obstruction via inhibition of macrophage infiltration. Cell Physiol Biochem 2016; 39:1837-1849.
16. Wang D, Xiong M, Chen C, Du L, Liu Z, Shi Y, et al. Legumain, an asparaginyl endopeptidase, mediates the effect of M2 macrophages on attenuating renal interstitial fibrosis in obstructive nephropathy. Kidney Int 2018; 94:91-101.
17. Wen Y, Lu X, Ren J, Privratsky JR, Yang B, Rudemiller NP, et al. KLF4 in macrophages attenuates tnfalpha-mediated kidney injury and fibrosis. J Am Soc Nephrol 2019; 30: 1925-1938.
18. Meng XM, Wang S, Huang XR, Yang C, Xiao J, Zhang Y, et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis 2016; 7:e2495.
19. Wang YY, Jiang H, Pan J, Huang XR, Wang YC, Huang HF, et al. Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. J Am Soc Nephrol 2017; 28:2053-2067.
20. Yin Y, Liu W, Dai Y. SOCS3 and its role in associated diseases. Hum Immunol 2015; 76:775-780.
21. Gao Y, Zhao H, Wang P, Wang J, Zou L. The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases. Scand J Immunol 2018; 88:e12727.
22. Pedroso JAB, Ramos-Lobo AM, Donato J. SOCS3 as a future target to treat metabolic disorders. Hormones (Athens) 2018; 18:127-136.
23. White GE, Cotterill A, Addley MR, Soilleux EJ, Greaves DR. Suppressor of cytokine signalling protein SOCS3 expression is increased at sites of acute and chronic inflammation. J Mol Histol 2011; 42:137-151.
24. Li S, Yu L, He A, Liu Q. Klotho inhibits unilateral ureteral obstruction-induced endothelial-to-mesenchymal transition via TGF-beta1/smad2/snail1 signaling in mice. Front Pharmacol 2019; 10:348-354.
25. Yao L, Wright MF, Farmer BC, Peterson LS, Khan AM, Zhong J, et al. Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction. Nephrol Dial Transplant 2019; 34:2042-2050.
26. Colon S, Luan H, Liu Y, Meyer C, Gewin L, Bhave G. Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model. Am J Physiol Renal Physiol 2018; 316: F360-F371.
27. Bhuvarahamurthy V, Kristiansen GO, Johannsen M, Loening SA, Schnorr D, Jung K, et al. In situ gene expression and localization of metalloproteinases MMP1, MMP2, MMP3, MMP9, and their inhibitors TIMP1 and TIMP2 in human renal cell carcinoma. Oncol Rep 2006; 15:1379-1384.
28. Reid AM, Juvonen R, Huuskonen P, Lehtonen M, Pasanen M, Lall N. In Vitro human metabolism and inhibition potency of verbascoside for cyp enzymes. Molecules 2019; 24: 2191-3208.
29. Akbay P, Calis I, Undeger U, Basaran N, Basaran AA. In vitro immunomodulatory activity of verbascoside from Nepeta ucrainica L. Phytother Res 2002; 16:593-595.
30. Attia YM, El-Kersh DM, Wagdy HA, Elmazar MM. Verbascoside: Identification, quantification, and potential sensitization of colorectal cancer cells to 5-fu by targeting pi3k/akt pathway. Sci Rep 2018; 8:1-12.
31. Alipieva K, Korkina L, Orhan IE, Georgiev MI. Verbascoside--a review of its occurrence, (bio)synthesis and pharmacological significance. Biotechnol Adv 2014; 32:1065-1076.
32. Paola RD, Oteri G, Mazzon E, Crisafulli C, Galuppo M, Toso RD, et al. Effects of verbascoside, biotechnologically purified by Syringa vulgaris plant cell cultures, in a rodent model of periodontitis. J Pharm Pharmacol 2011; 63:707-717.
33. Mechri B, Tekaya M, Hammami M, Chehab H. Root verbascoside and oleuropein are potential indicators of drought resistance in olive trees (Olea europaea L.). Plant Physiol Biochem 2019; 141:407-414.
34. Yang L, Zhang B, Liu J, Dong Y, Li Y, Li N, et al. Protective effect of acteoside on ovariectomy-induced bone loss in mice. Int J Mol Sci 2019; 20: 2974.
35. Khullar M, Sharma A, Wani A, Sharma N, Sharma N, Chandan BK, et al. Acteoside ameliorates inflammatory responses through NFkB pathway in alcohol induced hepatic damage. Int Immunopharmacol 2019; 69:109-117.
36. Hosseinian S, Shahraki S, Ebrahimzadeh Bideskan A, Shafei MN, Sadeghnia HR, Soukhtanloo M, et al. Thymoquinone alleviates renal interstitial fibrosis and kidney dysfunction in rats with unilateral ureteral obstruction. Phytother Res. 2019; 33:2023-2033.
37. Liu M, Zhu Y, Sun Y, Wen Z, Huang S, Guixia, et al. MnTBAP therapy attenuates the downregulation of sodium transporters in obstructive kidney disease. Oncotarget 2018; 9:394-403.
38. Ma X, Chang Y, Xiong Y, Wang Z, Wang X, Xu Q. Eplerenone ameliorates cell pyroptosis in contralateral kidneys of rats with unilateral ureteral obstruction. Nephron 2019; 142:233-242.
39. Kinter M, Wolstenholme JT, Thornhill BA, Newton EA, McCormick ML, Chevalier RL. Unilateral ureteral obstruction impairs renal antioxidant enzyme activation during sodium depletion. Kidney Int 1999; 55:1327-1334.
40. Rouschop KM, Sewnath ME, Claessen N, Roelofs JJ, Hoedemaeker I, van der Neut R, et al. CD44 deficiency increases tubular damage but reduces renal fibrosis in obstructive nephropathy. J Am Soc Nephrol 2004; 15:674-686.
41. Singh N, Shukla N, Singh P, Sharma R, Rajendran SM, Maurya R, et al. Verbascoside isolated from Tectona grandis mediates gastric protection in rats via inhibiting proton pump activity. Fitoterapia 2010; 81:755-761.
42. Xia D, Zhang Z, Zhao aY. Acteoside Attenuates oxidative stress and neuronal apoptosis in rats with focal cerebral ischemia - reperfusion injury. Biol Pharm Bull 2018; 41:1645-1651.
43. Wang L, Ren X, Tian XF, Cheng XL, Zhao YY, Li QY, et al. Protective effects of GPR120 agonist-programmed macrophages on renal interstitial fibrosis in unilateral ureteral obstruction (UUO) rats. Biomed Pharmacother 2019; 117:109172.
44. Li Y, Liu J, Yu T, Yan B, Li H. Interleukin-33 promotes obstructive renal injury via macrophages. Mol Med Rep 2019; 20:1353-1362.
45. Wiezel D, Assadi MH, Landau D, Troib A, Kachko L, Rabkin R, et al. Impaired renal growth hormone JAK/STAT5 signaling in chronic kidney disease. Nephrol Dial Transplant 2014; 29:791-799.
46. Yang SX, Zhang ZC, Bai HL. ClC-5 alleviates renal fibrosis in unilateral ureteral obstruction mice. Hum Cell 2019; 32:297-305.
47. Tammaro A, Florquin S, Brok M, Claessen N, Butter LM, Teske GJD, et al. S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy. Clin Exp Immunol 2018; 193:361-375.
48. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 2011; 7:684-696.
49. Wang W, Zhou P-H, Hu W, Xu C-G, Zhou X-J, Liang C-Z, et al. Cryptotanshinone hinders renal fibrosis and epithelial transdifferentiation in obstructive nephropathy by inhibiting TGF-β1/Smad3/integrin β1 signal. Oncotarget. 2018; 9:26625-26637.
50. de Moura Sperotto ND, Steffens L, Veríssimo RM, Henn JG, Péres VF, Vianna P, et al. Wound healing and anti-inflammatory activities induced by a Plantago australis hydroethanolic extract standardized in verbascoside. J Ethnopharmacol 2018; 225:178-188.
51. Dimitrova P, Alipieva K, Stojanov K, Milanova V, Georgiev MI. Plant-derived verbascoside and isoverbascoside regulate Toll-like receptor 2 and 4-driven neutrophils priming and activation. Phytomedicine 2019; 55:105-118.
52. Spínola V, Castilho PC. Madeira moneywort (Sibthorpia peregrina L.) as a new source of verbascoside and its derivatives with potential phyto-pharmaceutical applications. Nat Prod Res 2019; 33:3321-3325.
53. Jia WQ, Wang ZT, Zou MM, Lin JH, Li YH, Zhang L, et al. Verbascoside inhibits glioblastoma cell proliferation, migration and invasion while promoting apoptosis through upregulation of protein tyrosine phosphatase shp-1 and inhibition of stat3 phosphorylation. Cell Physiol Biochem 2018; 47:1871-1882.
54. Li M, Zhou F, Xu T, Song H, Lu B. Acteoside protects against 6-OHDA-induced dopaminergic neuron damage via Nrf2-ARE signaling pathway. Food Chem Toxicol 2018;119:6-13.
55. Nishida M, Okumura Y, Fujimoto S-i, Shiraishi I, Itoi T, Hamaoka K. Adoptive transfer of macrophages ameliorates renal fibrosis in mice. Biochem Biophys Res Commun 2005; 332:11-16.
56. Nan Si, Hajime Kanazawa, Katsuki Okuyama, Keisuke Imada, Hongjie Wang bJY, Haiyu Zhao, et al. Involvement of catechols in acteoside in the activation of promatrix metalloproteinase-2 and membrane type-1-matrix metalloproteinase expression via a phosphatidylinositol-3-kinase pathway in human dermal fibroblasts. Biol Pharm Bull. 2018; 41:1530-1536.
57. Alston CI, Dix RD. SOCS and herpesviruses, with emphasis on cytomegalovirus retinitis. Front Immunol 2019; 10:732.
58. Illanueva EC, Myers MG, Jr. Leptin receptor signaling and the regulation of mammalian physiology. Int J Obes (Lond) 2008; 32 Suppl 7: S8-S12.