Dulaglutide markedly prevents peritoneal fibrosis in a rodent model of chronic kidney disease: Insights into the pathogenesis

Yang,Chih-Chao; Yue,Ya; Wang,Yi-Ting; Chiang,John Y.; Cheng,Ben-Chung; Hsu,Tsuen-Wei; Chen,Yi-Ling; Li,Yi-Chen; Yip,Hon-Kan

doi:10.3892/ijmm.2025.5592

Dulaglutide markedly prevents peritoneal fibrosis in a rodent model of chronic kidney disease: Insights into the pathogenesis

Authors:
- Chih-Chao Yang
- Ya Yue
- Yi-Ting Wang
- John Y. Chiang
- Ben-Chung Cheng
- Tsuen-Wei Hsu
- Yi-Ling Chen
- Yi-Chen Li
- Hon-Kan Yip
View Affiliations

Affiliations: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 83301, Taiwan, R.O.C., Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, R.O.C., Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan, R.O.C., Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C.
Published online on: July 21, 2025 https://doi.org/10.3892/ijmm.2025.5592
Article Number: 151
Copyright: © Yang 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

Peritoneal fibrosis (PF) is a major complication of long-term peritoneal dialysis, leading to ultrafiltration failure and technique dropout, highlighting the urgent need for therapies that can preserve peritoneal membrane function and longevity. The present study evaluated the effectiveness of dulaglutide in preserving the functional integrity and durability of the peritoneum while inhibiting PF. In vitro Met-5A cells showed significant upregulation of inflammatory, oxidative stress, intracellular and mitochondrial reactive oxygen species (ROS), fibrotic, intracellular cytoskeletal, apoptotic and epithelial-mesenchymal transition (EMT) biomarkers, and dipeptidyl peptidase 4 (DPP4), following stimulation with a uremic toxin (p-Cresol), PF inducer [chlorhexidine gluconate (CG)] or endotoxin [lipopolysaccharide (LPS)]. Notably, these effects were significantly suppressed by dulaglutide or TGF-β/DPP4 double silencing. Furthermore, cell viability and glucagon-like peptide 1 (GLP-1) expression displayed an opposite pattern to ROS among the groups. Sprague-Dawley rats were divided into the following groups: i) Sham control (SC); ii) chronic kidney disease (CKD); iii) CKD + CG (mimicking renal failure and PF); and iv) CKD + CG + dulaglutide, and were euthanized by day 42. At this time point, the highest levels of peritoneal protein expression levels of oxidative stress (NOX-1, NOX-2 and DPP4), inflammation (NF-κB and TNF-α), angiogenesis (CD31 and von Willebrand factor) and EMT (TGF-β, Snail, β-catenin, vimentin, phosphorylated-Smad3, α-smooth muscle actin, collagen I, N-cadherin and fibronectin) factors; and cellular expression levels of fibrosis and inflammation markers, were observed in the CKD + CG group, the lowest were detected in the SC group, and the levels were significantly reduced in the CKD + CG + dulaglutide group compared with those in the CKD group. Furthermore, the expression levels of antioxidant proteins (nuclear factor erythroid 2-related factor 2, NAD(P)H quinone oxidoreductase 1 and GLP-1 receptor) exhibited an opposite trend to ROS-associated proteins among the groups. Additional Sprague-Dawley rats were categorized into the following groups: i) SC; ii) LPS-induced peritonitis; iii) LPS-induced peritonitis + dulaglutide, and were euthanized by day 5 after peritonitis induction. At this time point, flow cytometry revealed significantly increased levels of inflammatory cells (CD11b/c⁺, myeloperoxidase⁺ and Ly6G⁺ cells) in the circulation and abdominal fluid, and increased peritoneal permeability in the LPS-induced peritonitis group compared with those in the SC group; these levels were significantly reversed in the LPS-induced peritonitis + dulaglutide group. In conclusion, dulaglutide may effectively maintain peritoneal integrity primarily by suppressing inflammation, oxidative stress, EMT and fibrosis.

View Figures

View References

1	Saran R, Robinson B, Abbott KC, Bragg-Gresham J, Chen X, Gipson D, Gu H, Hirth RA, Hutton D, Jin Y, et al: US renal data system 2019 annual data report: Epidemiology of kidney disease in the United States. Am J Kidney Dis. 75(Suppl): A6–A7. 2020. View Article : Google Scholar
2	McCullough KP, Morgenstern H, Saran R, Herman WH and Robinson BM: Projecting ESRD incidence and prevalence in the United States through 2030. J Am Soc Nephrol. 30:127–135. 2019. View Article : Google Scholar :
3	Pozzoni P, Del Vecchio L, Pontoriero G, Di Filippo S and Locatelli F: Long-term outcome in hemodialysis: Morbidity and mortality. J Nephrol. 17:S87–S95. 2004.PubMed/NCBI
4	Deb S, Wijeysundera HC, Ko DT, Tsubota H, Hill S and Fremes SE: Coronary artery bypass graft surgery vs percutaneous interventions in coronary revascularization: A systematic review. JAMA. 310:2086–2095. 2013. View Article : Google Scholar : PubMed/NCBI
5	Hori D, Yamaguchi A and Adachi H: Coronary artery bypass surgery in end-stage renal disease patients. Ann Vasc Dis. 10:79–87. 2017. View Article : Google Scholar : PubMed/NCBI
6	Pang PYK, Teow CKJ, Huang MJ, Naik MJ, Lim SL, Chao VTT, Tan TE, Chua YL and Sin YK: Long-term prognosis in patients with end-stage renal disease after coronary artery bypass grafting. J Thorac Dis. 12:6722–6730. 2020. View Article : Google Scholar : PubMed/NCBI
7	Serafinceanu C, Neculaescu C, Cimponeriu D, Timar R and Covic AC: Impact of gender and dialysis modality on early mortality risk in diabetic ESRD patients: Data from a large single center cohort. Int Urol Nephrol. 46:607–614. 2014. View Article : Google Scholar
8	Tsur N, Menashe I and Haviv YS: Risk factors before dialysis predominate as mortality predictors in diabetic maintenance dialysis patients. Sci Rep. 9:106332019. View Article : Google Scholar : PubMed/NCBI
9	Schena FP: Epidemiology of end-stage renal disease: International comparisons of renal replacement therapy. Kidney Int. 57:S39–S45. 2000. View Article : Google Scholar
10	Vaios V, Georgianos PI, Liakopoulos V and Agarwal R: Assessment and management of hypertension among patients on peritoneal dialysis. Clin J Am Soc Nephrol. 14:297–305. 2019. View Article : Google Scholar :
11	McKane W, Chandna SM, Tattersall JE, Greenwood RN and Farrington K: Identical decline of residual renal function in high-flux biocompatible hemodialysis and CAPD. Kidney Int. 61:256–265. 2002. View Article : Google Scholar : PubMed/NCBI
12	Coentrão L, Van Biesen W, Nistor I, Tordoir J, Gallieni M, Marti Monros A and Bolignano D: Preferred haemodialysis vascular access for diabetic chronic kidney disease patients: A systematic literature review. J Vasc Access. 16:259–264. 2015. View Article : Google Scholar : PubMed/NCBI
13	Almasri J, Alsawas M, Mainou M, Mustafa RA, Wang Z, Woo K, Cull DL and Murad MH: Outcomes of vascular access for hemodialysis: A systematic review and meta-analysis. J Vasc Surg. 64:236–243. 2016. View Article : Google Scholar : PubMed/NCBI
14	Arhuidese IJ, Orandi BJ, Nejim B and Malas M: Utilization, patency, and complications associated with vascular access for hemodialysis in the United States. J Vasc Surg. 68:1166–1174. 2018. View Article : Google Scholar : PubMed/NCBI
15	Arhuidese IJ, Purohit A, Elemuo C, Parkerson GR, Shames ML and Malas MB: Outcomes of autogenous fistulas and prosthetic grafts for hemodialysis access in diabetic and nondiabetic patients. J Vasc Surg. 72:2088–2096. 2020. View Article : Google Scholar : PubMed/NCBI
16	Li YC, Sung PH, Yang YH, Chiang JY, Yip HK and Yang CC: Dipeptidyl peptidase 4 promotes peritoneal fibrosis and its inhibitions prevent failure of peritoneal dialysis. Commun Biol. 4:1442021. View Article : Google Scholar : PubMed/NCBI
17	Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, Mackenzie RK and Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol. 13:470–479. 2002. View Article : Google Scholar : PubMed/NCBI
18	Williams JD, Craig KJ, von Ruhland C, Topley N and Williams GT; Biopsy Registry Study Group: The natural course of peritoneal membrane biology during peritoneal dialysis. Kidney Int. (Suppl): S43–S49. 2003. View Article : Google Scholar
19	Mutsaers SE, Birnie K, Lansley S, Herrick SE, Lim CB and Prêle CM: Mesothelial cells in tissue repair and fibrosis. Front Pharmacol. 6:1132015. View Article : Google Scholar : PubMed/NCBI
20	Di Paolo N and Sacchi G: Atlas of peritoneal histology. Perit Dial Int. 20:S5–S96. 2000.PubMed/NCBI
21	Yung S and Chan TM: Pathophysiological changes to the peritoneal membrane during PD-related peritonitis: The role of mesothelial cells. Mediators Inflamm. 2012:4841672012. View Article : Google Scholar : PubMed/NCBI
22	Terri M, Trionfetti F, Montaldo C, Cordani M, Tripodi M, Lopez-Cabrera M and Strippoli R: Mechanisms of peritoneal fibrosis: Focus on immune cells-peritoneal stroma interactions. Front Immunol. 12:6072042021. View Article : Google Scholar : PubMed/NCBI
23	Stone RC, Pastar I, Ojeh N, Chen V, Liu S, Garzon KI and Tomic-Canic M: Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 365:495–506. 2016. View Article : Google Scholar : PubMed/NCBI
24	Li M, Luan F, Zhao Y, Hao H, Zhou Y, Han W and Fu X: Epithelial-mesenchymal transition: An emerging target in tissue fibrosis. Exp Biol Med (Maywood). 241:1–13. 2016. View Article : Google Scholar
25	Milan Manani S, Virzi GM, Giuliani A, Baretta M, Corradi V, De Cal M, Biasi C, Crepaldi C and Ronco C: Lipopolysaccharide evaluation in peritoneal dialysis patients with peritonitis. Blood Purif. 49:434–439. 2020. View Article : Google Scholar : PubMed/NCBI
26	Knapp S, de Vos AF, Florquin S, Golenbock DT and van der Poll T: Lipopolysaccharide binding protein is an essential component of the innate immune response to escherichia coli peritonitis in mice. Infect Immun. 71:6747–6753. 2003. View Article : Google Scholar : PubMed/NCBI
27	Shen WR, Kimura K, Ishida M, Sugisawa H, Kishikawa A, Shima K, Ogawa S, Qi J and Kitaura H: The glucagon-like peptide-1 receptor agonist exendin-4 inhibits lipopolysaccharide-induced osteoclast formation and bone resorption via inhibition of TNF-α expression in macrophages. J Immunol Res. 2018:57836392018. View Article : Google Scholar
28	Mehdi SF, Pusapati S, Anwar MS, Lohana D, Kumar P, Nandula SA, Nawaz FK, Tracey K, Yang H, LeRoith D, et al: Glucagon-like peptide-1: A multi-faceted anti-inflammatory agent. Front Immunol. 14:11482092023. View Article : Google Scholar : PubMed/NCBI
29	Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C and Gao J: Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduct Target Ther. 9:2342024. View Article : Google Scholar : PubMed/NCBI
30	Chen YT, Tsai TH, Yang CC, Sun CK, Chang LT, Chen HH, Chang CL, Sung PH, Zhen YY, Leu S, et al: Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med. 11:2702013. View Article : Google Scholar : PubMed/NCBI
31	Yip HK, Yang CC, Chen KH, Huang TH, Chen YL, Zhen YY, Sung PH, Chiang HJ, Sheu JJ, Chang CL, et al: Combined melatonin and exendin-4 therapy preserves renal ultrastructural integrity after ischemia-reperfusion injury in the male rat. J Pineal Res. 59:434–447. 2015. View Article : Google Scholar : PubMed/NCBI
32	Chang YC, Hsu SY, Yang CC, Sung PH, Chen YL, Huang TH, Kao GS, Chen SY, Chen KH, Chiang HJ, et al: Enhanced protection against renal ischemia-reperfusion injury with combined melatonin and exendin-4 in a rodent model. Exp Biol Med (Maywood). 241:1588–1602. 2016. View Article : Google Scholar : PubMed/NCBI
33	Zhen YY, Yang CC, Hung CC, Lee CC, Lee CC, Wu CH, Chen YT, Chen WY, Chen KH, Yip HK and Ko SF: Extendin-4 protects kidney from acute ischemia-reperfusion injury through upregulation of NRF2 signaling. Am J Transl Res. 9:4756–4771. 2017.PubMed/NCBI
34	Sung PH, Chiang HJ, Wallace CG, Yang CC, Chen YT, Chen KH, Chen CH, Shao PL, Chen YL, Chua S, et al: Exendin-4-assisted adipose derived mesenchymal stem cell therapy protects renal function against co-existing acute kidney ischemia-reperfusion injury and severe sepsis syndrome in rat. Am J Transl Res. 9:3167–3183. 2017.PubMed/NCBI
35	Yang CC, Chen YT, Wallace CG, Chen KH, Cheng BC, Sung PH, Li YC, Ko SF, Chang HW and Yip HK: Early administration of empagliflozin preserved heart function in cardiorenal syndrome in rat. Biomed Pharmacother. 109:658–670. 2019. View Article : Google Scholar
36	Yin TC, Sung PH, Chen KH, Li YC, Luo CW, Huang CR, Sheu JJ, Chiang JY, Lee MS and Yip HK: Extracorporeal shock wave-assisted adipose-derived fresh stromal vascular fraction restores the blood flow of critical limb ischemia in rat. Vascul Pharmacol. 113:57–69. 2019. View Article : Google Scholar : PubMed/NCBI
37	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the care and use of laboratory animals: Eighth edition. The National Academies Press; Washington, DC: 2011
38	Huang TH, Chen YT, Sung PH, Chiang HJ, Chen YL, Chai HT, Chung SY, Tsai TH, Yang CC, Chen CH, et al: Peripheral blood-derived endothelial progenitor cell therapy prevented deterioration of chronic kidney disease in rats. Am J Transl Res. 7:804–824. 2015.PubMed/NCBI
39	Chang CL, Sung PH, Sun CK, Chen CH, Chiang HJ, Huang TH, Chen YL, Zhen YY, Chai HT, Chung SY, et al: Protective effect of melatonin-supported adipose-derived mesenchymal stem cells against small bowel ischemia-reperfusion injury in rat. J Pineal Res. 59:206–220. 2015. View Article : Google Scholar : PubMed/NCBI
40	Yue Y, Yeh JN, Chiang JY, Sung PH, Chen YL, Liu F and Yip HK: Intrarenal arterial administration of human umbilical cord-derived mesenchymal stem cells effectively preserved the residual renal function of diabetic kidney disease in rat. Stem Cell Res Ther. 13:1862022. View Article : Google Scholar : PubMed/NCBI
41	Lin KC, Yeh JN, Shao PL, Chiang JY, Sung PH, Huang CR, Chen YL, Yip HK and Guo J: Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs. J Cell Mol Med. 27:1110–1130. 2023. View Article : Google Scholar : PubMed/NCBI
42	Sung PH, Cheng BC, Hsu TW, Chiang JY, Chiang HJ, Chen YL, Yang CC and Yip HK: Oxidized-LDL deteriorated the renal residual function and parenchyma in CKD rat through upregulating epithelial mesenchymal transition and extracellular matrix-mediated tubulointerstitial fibrosis-pharmacomodulation of rosuvastatin. Antioxidants (Basel). 11:24652022. View Article : Google Scholar : PubMed/NCBI
43	Sung PH, Sun CK, Ko SF, Chang LT, Sheu JJ, Lee FY, Wu CJ, Chua S and Yip HK: Impact of hyperglycemic control on left ventricular myocardium. A molecular and cellular basic study in a diabetic rat model. Int Heart J. 50:191–206. 2009. View Article : Google Scholar : PubMed/NCBI
44	Sheu JJ, Yang CC, Wallace CG, Chen KH, Shao PL, Sung PH, Li YC, Chu YC, Guo J and Yip HK: Uremic toxic substances are essential elements for enhancing carotid artery stenosis after balloon-induced endothelial denudation: Worsening role of the adventitial layer. Am J Transl Res. 12:7144–7159. 2020.PubMed/NCBI
45	Yip HK, Lee MS, Li YC, Shao PL, Chiang JY, Sung PH, Yang CH and Chen KH: Dipeptidyl peptidase-4 deficiency effectively protects the brain and neurological function in rodent after acute hemorrhagic stroke. Int J Biol Sci. 16:3116–3132. 2020. View Article : Google Scholar : PubMed/NCBI
46	Ko SF, Chen KH, Wallace CG, Yang CC, Sung PH, Shao PL, Li YC, Chen YT and Yip HK: Protective effect of combined therapy with hyperbaric oxygen and autologous adipose-derived mesenchymal stem cells on renal function in rodent after acute ischemia-reperfusion injury. Am J Transl Res. 12:3272–3287. 2020.PubMed/NCBI
47	Vanholder R, Pletinck A, Schepers E and Glorieux G: Biochemical and clinical impact of organic uremic retention solutes: A comprehensive update. Toxins (Basel). 10:332018. View Article : Google Scholar : PubMed/NCBI
48	Chen YT, Wallace CG, Yang CC, Chen CH, Chen KH, Sung PH, Chen YL, Chai HT, Chung SY, Chua S, et al: DPP-4 enzyme deficiency protects kidney from acute ischemia-reperfusion injury: Role for remote intermittent bowel ischemia-reperfusion preconditioning. Oncotarget. 8:54821–54837. 2017. View Article : Google Scholar : PubMed/NCBI
49	Chang MW, Chen CH, Chen YC, Wu YC, Zhen YY, Leu S, Tsai TH, Ko SF, Sung PH, Yang CC, et al: Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors. Acta Pharmacol Sin. 36:119–130. 2015. View Article : Google Scholar :