Procyanidin B2 suppresses hyperglycemia‑induced renal mesangial cell dysfunction by modulating CAV‑1‑dependent signaling

Yin,Jun; Wang,Ke; Zhu,Xue; Lu,Guoyuan; Jin,Donghua; Qiu,Junsi; Zhou,Fanfan

doi:10.3892/etm.2022.11423

Procyanidin B2 suppresses hyperglycemia‑induced renal mesangial cell dysfunction by modulating CAV‑1‑dependent signaling

Authors:
- Jun Yin
- Ke Wang
- Xue Zhu
- Guoyuan Lu
- Donghua Jin
- Junsi Qiu
- Fanfan Zhou
View Affiliations

Affiliations: Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, P.R. China, Department of Nephrology, People's Hospital of Suzhou New District, Suzhou, Jiangsu 215129, P.R. China, Department of Nephrology, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China, Sydney Pharmacy School, The University of Sydney, Sydney, New South Wales A-2006, Australia
Published online on: June 7, 2022 https://doi.org/10.3892/etm.2022.11423
Article Number: 496
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The dysfunction of renal mesangial cells (MCs) is a hallmark of diabetic kidney disease (DKD), which triggers glomerulosclerosis leading to end‑stage renal disease. Procyanidin B2 (PB2), the main component of proanthocyanidin, is well known for its antioxidant and anti‑inflammatory effects; however, it remains unclear as to whether it has protective effects on DKD. The present study investigated the protective effect of PB2 against hyperglycemia‑induced renal MC dysfunction in mouse SV40‑Mes13 (Mes13) cells. The Mes13 cells were treated with or without PB2 under HG conditions. Cell proliferation was assessed using an MTT assay and oxidative stress was assessed by examining intracellular ROS generation and H₂O₂ production. The changes in extracellular matrix accumulation‑ and cellular inflammation‑related proteins were measured by western blot analysis, ELISA and immunofluorescence analysis. The results showed that PB2 treatment markedly attenuated hyperglycemia‑induced cell proliferation, oxidative stress, extracellular matrix accumulation and cellular inflammation in Mes13 cells, which was accompanied by an inactivation of redoxosomes, TGF‑β1/SMAD and IL‑1β/TNF‑α/NF‑κB signaling pathways. The present study also demonstrated that hyperglycemia upregulated and activated caveolin‑1 (CAV‑1), whereas PB2 treatment potently reversed this effect. In accordance, CAV‑1 overexpression abolished the protective effects of PB2 against hyperglycemia in Mes13 cells, indicating that the cytoprotective effect of PB2 was CAV‑1‑dependent. These findings form the basis of the potential clinical applications of PB2 in the treatment of DKD.

View Figures

View References

1	Alicic RZ, Rooney MT and Tuttle KR: Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 12:2032–2045. 2017.PubMed/NCBI View Article : Google Scholar
2	Lin YC, Chang YH, Yang SY, Wu KD and Chu TS: Update of pathophysiology and management of diabetic kidney disease. J Formos Med Assoc. 117:662–675. 2018.PubMed/NCBI View Article : Google Scholar
3	Anders HJ, Huber TB, Isermann B and Schiffer M: CKD in diabetes: Diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol. 14:361–377. 2018.PubMed/NCBI View Article : Google Scholar
4	Zhao JH: Mesangial cells and renal fibrosis. Adv Exp Med Biol. 1165:165–194. 2019.PubMed/NCBI View Article : Google Scholar
5	Dong Z, Sun Y, Wei G, Li S and Zhao Z: Ergosterol ameliorates diabetic nephropathy by attenuating mesangial cell proliferation and extracellular matrix deposition via the TGF-β1/Smad2 signaling pathway. Nutrients. 11(483)2019.PubMed/NCBI View Article : Google Scholar
6	Marciano DK: Mesangial cells: The tuft guys of glomerular development. J Am Soc Nephrol. 30:1551–1553. 2019.PubMed/NCBI View Article : Google Scholar
7	Tung CW, Hsu YC, Shih YH, Chang PJ and Lin CL: Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton). 23 (Suppl 4):S32–S37. 2018.PubMed/NCBI View Article : Google Scholar
8	Parton RG, Tillu VA and Collins BM: Caveolae. Curr Biol. 28:R402–R405. 2018.PubMed/NCBI View Article : Google Scholar
9	Parton RG, McMahon KA and Wu Y: Caveolae: Formation, dynamics, and function. Curr Opin Cell Biol. 65:8–16. 2020.PubMed/NCBI View Article : Google Scholar
10	Wang S, Wang N, Zheng Y, Zhang J, Zhang F and Wang Z: Caveolin-1: An oxidative stress-related target for cancer prevention. Oxid Med Cell Longev. 2017(7454031)2017.PubMed/NCBI View Article : Google Scholar
11	Peng F, Wu D, Ingram AJ, Zhang B, Gao B and Krepinsky JC: RhoA activation in mesangial cells by mechanical strain depends on caveolae and caveolin-1 interaction. J Am Soc Nephrol. 18:189–198. 2007.PubMed/NCBI View Article : Google Scholar
12	Mehta N, Zhang D, Li R, Wang T, Gava A, Parthasarathy P, Gao B and Krepinsky JC: Caveolin-1 regulation of Sp1 controls production of the antifibrotic protein follistatin in kidney mesangial cells. Cell Commun Signal. 17(37)2019.PubMed/NCBI View Article : Google Scholar
13	Sun LN, Liu XC, Chen XJ, Guan GJ and Liu G: Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS. Acta Pharmacol Sin. 37:645–655. 2016.PubMed/NCBI View Article : Google Scholar
14	Rauf A, Imran M, Abu-Izneid T, Iahtisham-Ul-Haq Patel S, Pan X, Naz S, Sanches Silva A, Saeed F and Rasul Suleria HA: Proanthocyanidins: A comprehensive review. Biomed Pharmacother. 116(108999)2019.PubMed/NCBI View Article : Google Scholar
15	Luca SV, Macovei I, Bujor A, Miron A, Skalicka-Woźniak K, Aprotosoaie AC and Trifan A: Bioactivity of dietary polyphenols: The role of metabolites. Crit Rev Food Sci Nutr. 60:626–659. 2020.PubMed/NCBI View Article : Google Scholar
16	Su H, Li Y, Hu D, Xie L, Ke H, Zheng X and Chen W: Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state. Free Radic Biol Med. 126:269–286. 2018.PubMed/NCBI View Article : Google Scholar
17	Bao L, Cai X, Zhang Z and Li Y: Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase-silent mating type information regulation 2 homologue 1-PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine. Br J Nutr. 113:35–44. 2014.PubMed/NCBI View Article : Google Scholar
18	Zhou Y, Li BY, Li XL, Wang YJ, Zhang Z, Pei F, Wang QZ, Zhang J, Cai YW, Cheng M and Gao HQ: Restoration of mimecan expression by grape seed procyanidin B2 through regulation of nuclear factor-kappaB in mice with diabetic nephropathy. Iran J Kidney Dis. 10:325–331. 2016.PubMed/NCBI
19	Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 91:1310–1316. 1999.PubMed/NCBI View Article : Google Scholar
20	Chen B, Li Y, Liu Y and Xu Z: circLRP6 regulates high glucose-induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells. J Cell Physiol. 234:21249–21259. 2019.PubMed/NCBI View Article : Google Scholar
21	Fan J, Liu H, Wang J, Zeng J, Tan Y, Wang Y, Yu X, Li W, Wang P, Yang Z and Dai X: Procyanidin B2 improves endothelial progenitor cell function and promotes wound healing in diabetic mice via activating Nrf2. J Cell Mol Med. 25:652–665. 2021.PubMed/NCBI View Article : Google Scholar
22	Yin M, Zhang P, Yu F, Zhang Z, Cai Q, Lu W, Li B, Qin W, Cheng M, Wang H and Gao H: Grape seed procyanidin B2 ameliorates hepatic lipid metabolism disorders in db/db mice. Mol Med Rep. 16:2844–2850. 2017.PubMed/NCBI View Article : Google Scholar
23	Zhang Z, Li BY, Li XL, Cheng M, Yu F, Lu WD, Cai Q, Wang JF, Zhou RH, Gao HQ and Shen L: Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy. Biochim Biophys Acta. 1832:805–816. 2013.PubMed/NCBI View Article : Google Scholar
24	Li D, Zhao T, Meng J, Jing Y, Jia F and He P: Procyanidin B2 inhibits high glucose-induced epithelial-mesenchymal transition in HK-2 human renal proximal tubular epithelial cells. Mol Med Rep. 12:8148–8154. 2015.PubMed/NCBI View Article : Google Scholar
25	Adebiyi A, Soni H, John TA and Yang F: Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells. Exp Cell Res. 324:92–104. 2014.PubMed/NCBI View Article : Google Scholar
26	Guan TH, Chen G, Gao B, Janssen MR, Uttarwar L, Ingram AJ and Krepinsky JC: Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy. Diabetologia. 56:2068–2077. 2013.PubMed/NCBI View Article : Google Scholar
27	Moriyama T, Tsuruta Y, Shimizu A, Itabashi M, Takei T, Horita S, Uchida K and Nitta K: The significance of caveolae in the glomeruli in glomerular disease. J Clin Pathol. 64:504–509. 2011.PubMed/NCBI View Article : Google Scholar
28	Li CD, Zhao JY, Chen JL, Lu JH, Zhang MB, Huang Q, Cao YN, Jia GL, Tao YX, Li J and Cao H: Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy. Endocrine. 64:55–66. 2019.PubMed/NCBI View Article : Google Scholar
29	Akaishi T, Abe M, Okuda H, Ishizawa K, Abe T, Ishii T and Ito S: High glucose level and angiotensin II type 1 receptor stimulation synergistically amplify oxidative stress in renal mesangial cells. Sci Rep. 9(5214)2019.PubMed/NCBI View Article : Google Scholar
30	Spencer NY and Engelhardt JF: The basic biology of redoxosomes in cytokine-mediated signal transduction and implications for disease-specific therapies. Biochemistry. 53:1551–1564. 2014.PubMed/NCBI View Article : Google Scholar
31	Oakley FD, Abbott D, Li Q and Engelhardt JF: Signaling components of redox active endosomes: The redoxosomes. Antioxid Redox Signal. 11:1313–1333. 2009.PubMed/NCBI View Article : Google Scholar
32	Dong J, Ding L, Wang L, Yang Z, Wang Y, Zang Y, Cao X and Tang L: Effects of bradykinin on proliferation, apoptosis, and cycle of glomerular mesangial cells via the TGF-β1/Smad signaling pathway. Turk J Biol. 45:17–25. 2021.PubMed/NCBI View Article : Google Scholar
33	Ma TT and Meng XM: TGF-β/Smad and renal fibrosis. Adv Exp Med Biol. 1165:347–364. 2019.PubMed/NCBI View Article : Google Scholar