Drug Design, Development and Therapy (Sep 2023)
Isoliensinine Attenuates Renal Fibrosis and Inhibits TGF-β1/Smad2/3 Signaling Pathway in Spontaneously Hypertensive Rats
Abstract
Mengying Yao,1– 3,* Dawei Lian,1– 3,* Meizhu Wu,1– 3 Yuting Zhou,1– 3 Yi Fang,1– 4 Siyu Zhang,1– 3 Wenqiang Zhang,1– 3 Yanyan Yang,1– 4 Renfeng Li,1– 3 Hong Chen,1– 3 Youqin Chen,5 Aling Shen,1– 4 Jun Peng1– 3 1Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 2Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 3Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China; 4Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 5Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA*These authors contributed equally to this workCorrespondence: Aling Shen; Jun Peng, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China, Tel +86 18050286255 ; +86 15806070011, Email [email protected]; [email protected]: This study aimed to investigate the molecular mechanisms of isoliensinine, a kind of bibenzyl isoquinoline alkaloid which isolated from a TCM named Lotus Plumule (Nelumbo nucifera Gaertn), in treating renal interstitial fibrosis (RIF) by using RNA sequencing, KEGG analysis and in vivo experimental approaches.Methods: Spontaneous hypertension rats (SHRs) were randomly assigned into five groups, consisting of SHR, SHR+Isoliensinine-L (2.5 mg/kg/day), SHR+Isoliensinine-M (5 mg/kg/day), SHR+Isoliensinine-H (10 mg/kg/day), and SHR+Valsartan (10 mg/kg/day) groups (n = 6 for each group). A control group of Wistar Kyoto rats (n = 6) was also included. Rats were treated intragastrically with isoliensinine, valsartan, or double-distilled water of equal volume for 10 weeks. To examine the therapeutic impact on hypertensive renal injury, fibrosis, and its underlying mechanisms, multiple techniques were employed, including hematoxylin and eosin staining, Masson trichrome staining, RNA sequencing, gene ontology (GO) function and pathway enrichment analysis and immunohistochemistry.Results: Resultantly, the use of isoliensinine at different concentrations or valsartan showed significant improvement in renal pathological injury in SHRs. RNA sequencing and KEGG analysis uncovered 583 differentially expressed transcripts and pathways enriched in collagen formation and ECM–receptor interaction after treatment with isoliensinine. There was also a reduction in the increase of collagen and upregulation of collagen I & III, TGF-β 1, p-Smad2, and p-Smad3 in the renal tissue of SHRs. Thus, isoliensinine ameliorated renal injury and collagen deposition in hypertensive rats, and inhibiting the activation of the TGF-β 1/Smad2/3 pathway might be one of the underlying mechanisms.Conclusion: This study showed that treatment with isoliensinine effectively reduced the renal injury and fibrosis in SHRs. In addition, isoliensinine inhibited the TGF-β 1/Smad2/3 signaling in-vivo. These findings provided strong evidence for the therapeutic benefits of isoliensinine in combating renal injury and fibrosis.Graphical Abstract: Keywords: isoliensinine, RNA sequencing, hypertension, renal injury, TGF-β 1/Smad2/3 pathway, collagen deposition
