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Identification of six hub genes and two key pathways in two rat renal fibrosis models based on bioinformatics and
Yueqin Cai1,2, Jingan Chen3, Jingyan Liu4
1School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Abstract:
Renal fibrosis (RF) is the common pathological manifestation and central treatment target of multiple chronic kidney diseases with high morbidity and mortality. Currently, the molecular mechanisms underlying RF remain poorly understood, and exploration of RF-related hub targets and pathways is urgently needed. In this study, two classical RF rat models (adenine and UUO) were established and evaluated by HE, Masson and immunohistochemical staining. To clear molecular mechanisms of RF, differentially expressed genes (DEGs) were identified using RNA-Seq analysis, hub targets and pathways were screened by bioinformatics (functional enrichment analyses, PPI network, and co-expression analysis), the screening results were verified by qRT-PCR, and potential drugs of RF were predicted by network pharmacology and molecular docking. The results illustrated that renal structures were severely damaged and fibrotic in adenine- and UUO-induced models, as evidenced by collagen deposition, enhanced expressions of biomarkers (TGF-β1 and α-SMA), reduction of E-cadherin biomarker, and severe renal function changes (significantly decreased UTP, CREA, Ccr, and ALB levels and increased UUN and BUN levels), etc. 1189 and 1253 RF-related DEGs were screened in the adenine and UUO models, respectively. Two key pathways (AGE-RAGE and NOD-like receptor) and their hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) were identified by PPI networks, co-expressed relationships, and qRT-PCR verification. Furthermore, various reported herbal ingredients (curcumin, resveratrol, honokiol, etc.) were considered as important drug candidates due to the strong binding affinity with these hub targets. Overall, this study mainly identified two key RF-related pathways (AGE-RAGE and NOD-like receptor), screened hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) that involved inflammation, ECM formation, myofibroblasts generation, and pyroptosis, etc., and provided referable drug candidates (curcumin, resveratrol, honokiol, etc.) in basic research and clinical treatment of RF.
Insights
This study identifies key pathways and targets in renal fibrosis (RF) using rat models. It highlights potential herbal drug candidates like curcumin for treating this common kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Renal fibrosis (RF) is a major cause of chronic kidney disease mortality.
- The molecular mechanisms driving RF are not fully understood, necessitating identification of key targets and pathways.
- Current treatment strategies for RF are limited, underscoring the need for novel therapeutic approaches.
Purpose of the Study:
- To elucidate the molecular mechanisms of renal fibrosis (RF).
- To identify key RF-related pathways and hub targets.
- To predict potential therapeutic drug candidates for RF.
Main Methods:
- Established adenine and UUO-induced rat models of renal fibrosis.
- Utilized RNA-Seq for differential gene expression analysis.
- Employed bioinformatics, including PPI networks and co-expression analysis, for target and pathway screening.
- Verified findings using qRT-PCR and predicted drug candidates via network pharmacology and molecular docking.
Main Results:
- Adenine and UUO models showed severe renal structural damage, collagen deposition, and altered biomarker expression (TGF-β1, α-SMA, E-cadherin).
- Identified 1189 and 1253 differentially expressed genes in the respective models.
- Discovered two key pathways, AGE-RAGE and NOD-like receptor, with hub targets including Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18.
- Predicted herbal compounds like curcumin, resveratrol, and honokiol as potential drug candidates with strong target binding affinities.
Conclusions:
- Identified AGE-RAGE and NOD-like receptor pathways as critical in renal fibrosis.
- Highlighted hub targets involved in inflammation, ECM formation, myofibroblast generation, and pyroptosis.
- Provided potential therapeutic strategies and drug candidates for RF management.
