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Updated: May 2, 2026
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Integrated causal inference, kidney transcriptomics, and experimental validation identify ChREBP (MLXIPL) as a driver
Mingliang Liu1, Shihang Chen2, Shi Wu2
1School of Medicine, Nankai University, Tianjin, China.
Background:
Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease despite advances in glucose-, blood pressure-, and albuminuria-lowering therapies. The glucose-responsive transcription factor carbohydrate response element-binding protein (ChREBP; encoded by MLXIPL) regulates glycolytic-lipogenic programs, yet its causal contribution to renal injury is challenging to disentangle in advanced DKD, where bulk kidney transcriptomes reflect tissue remodeling and cellular compositional shifts.
Methods:
We integrated two-sample Mendelian randomization (MR), kidney transcriptomic stratification, network analyses, and experimental validation. MR used blood cis-eQTL instruments for MLXIPL to estimate causal effects on type 2 diabetes (T2D) and urinary albumin-to-creatinine ratio (UACR), including a non-diabetic UACR stratum. In kidney transcriptomics (GSE30529), we evaluated remodeling-related confounding and applied within-DKD, median-based MLXIPL-high/low stratification for GSEA/GSVA and functional/network inference. Key observations were validated in db/db mice and primary proximal tubular epithelial cells (PTECs) exposed to high glucose with matched osmotic control.
Results:
Genetically predicted higher MLXIPL expression was associated with increased T2D risk across multiple phenotype definitions and with higher UACR, including replication in non-diabetic individuals. Within DKD, MLXIPL heterogeneity tracked metabolic programs by GSEA and divergent pathway activity by GSVA, while signatures related to profibrotic and proliferative remodeling were concomitantly enriched in the low-MLXIPL subgroup. Network analyses positioned MLXIPL/ChREBP within a dense metabolic interaction and regulatory landscape. Experimentally, ChREBP and Mlxipl were increased in db/db kidneys and induced by high glucose in PTECs, accompanied by coordinated upregulation of lipogenic targets (Acly, Acaca, Fasn, Srebf1) and an inverse relationship with Ppargc1b.
Conclusions:
Integrating genetic inference, confounding-aware kidney transcriptomics, network biology, and experimental validation, our study supports MLXIPL/ChREBP as a pathogenic nutrient-sensing node linking diabetes susceptibility to renal injury and maladaptive metabolic remodeling in DKD, providing a mechanistic rationale for targeting this axis to mitigate residual renal risk.
Insights
Carbohydrate response element-binding protein (ChREBP) links diabetes to kidney injury by promoting maladaptive metabolic remodeling. Targeting this nutrient-sensing pathway may reduce residual renal risk in diabetic kidney disease.
Area of Science:
- Metabolic regulation
- Renal pathophysiology
- Genetic epidemiology
Background:
- Diabetic kidney disease (DKD) is a major cause of end-stage renal disease, with current therapies offering incomplete protection.
- The role of the glucose-responsive transcription factor ChREBP (encoded by MLXIPL) in advanced DKD is unclear due to confounding factors like tissue remodeling.
Purpose of the Study:
- To investigate the causal role of MLXIPL/ChREBP in diabetic kidney disease pathogenesis.
- To elucidate the molecular mechanisms linking ChREBP activity to renal injury and metabolic dysfunction in DKD.
Main Methods:
- Two-sample Mendelian randomization (MR) using blood cis-eQTLs for MLXIPL to assess causal effects on type 2 diabetes and albuminuria.
- Kidney transcriptomic stratification (GSE30529) with MLXIPL-high/low groups within DKD for gene set enrichment and gene set variation analysis.
- Experimental validation in db/db mice and high glucose-exposed primary proximal tubular epithelial cells (PTECs).
Main Results:
- Genetically predicted higher MLXIPL expression associated with increased type 2 diabetes risk and urinary albumin-to-creatinine ratio (UACR).
- Within DKD, MLXIPL heterogeneity correlated with metabolic programs; lower MLXIPL was linked to profibrotic and proliferative remodeling signatures.
- ChREBP and MLXIPL were upregulated in mouse kidneys and PTECs under high glucose, driving lipogenic gene expression and inversely correlating with Ppargc1b.
Conclusions:
- MLXIPL/ChREBP acts as a pathogenic nutrient-sensing node connecting diabetes susceptibility to renal injury.
- The study provides a mechanistic rationale for targeting the MLXIPL/ChREBP axis to mitigate residual renal risk in DKD.
- This research integrates genetic, transcriptomic, and experimental data to understand DKD pathogenesis.
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