Heterogeneity characterization and key pathogenic genes screening based on diabetic nephropathy microenvironment

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• Diabetic nephropathy (DN) is characterized by inflammatory response and immune/stromal cell infiltration in renal tissues.
• Understanding the heterogeneity of the DN microenvironment is crucial for exploring disease mechanisms.

Purpose of the Study:

• To classify DN samples based on immune and stromal cell infiltration.
• To describe DN microenvironment heterogeneity and explore phenotypic differentiation mechanisms.
• To screen key pathogenic genes, construct a scoring model, and investigate their role in DN.

Main Methods:

• Utilized RNA sequencing datasets (GSE142025, GSE96804) from GEO database.
• Employed the xCell algorithm for immune and stromal cell infiltration data.
• Applied consensus clustering (Ward's method) and principal component analysis (PCA) for classification and scoring model construction.

Main Results:

• Identified 15 key pathogenic genes (e.g., FN1, EGR1, ABCC9) in DN.
• Developed a PCA-based score effectively distinguishing normal from DN samples (AUC=0.90) and DN subtypes (AUC=0.99).
• Demonstrated that ABCC9 knockdown counteracted high glucose-induced mesangial cell apoptosis and migration.

Conclusions:

• The identified genes and PCA score offer a quantitative method to describe the DN microenvironment and disease progression.
• The study highlights ABCC9 as a potential therapeutic target for mitigating high-glucose-induced damage in DN.