Glomerular Transcriptome Analysis Reveals Endothelial Disturbances in Patients With Idiopathic Nephrotic Syndrome

Area of Science:

• Nephrology and Molecular Biology
• Glomerular Disease Pathogenesis
• Endothelial Biology

Background:

• Idiopathic nephrotic syndrome (INS) is traditionally considered a podocyte-specific disease.
• Emerging evidence suggests endothelial involvement, but its precise role and significance remain unclear.
• Understanding the molecular mechanisms of endothelial dysfunction in INS is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the glomerular expression of genes critical for endothelial health in patients with INS.
• To explore the relationship between the expression of these endothelial genes and clinical markers of disease severity, including kidney function and histological damage.
• To validate findings in experimental models of INS.

Main Methods:

• Cross-sectional study of 70 minimal change disease and 83 focal segmental glomerulosclerosis patients from the Nephrotic Syndrome Study Network cohort, plus 53 controls.
• Gene expression analysis of 10 key endothelial-related genes (e.g., NOS3, HPSE, ICAM1) from micro-dissected human glomeruli.
• Validation using animal models and cultured glomerular endothelial cells exposed to INS sera.

Main Results:

• Most investigated endothelial genes were upregulated in INS glomeruli compared to controls, with ESM1 and MMP9 showing decreased expression.
• Expression of endothelial genes correlated with markers of glycocalyx injury, cell activation, and ultrastructural damage.
• Specific gene expressions (HPSE, ADAMTS1, ICAM1, CAV1) were inversely associated with kidney function and positively with proteinuria, podocyte injury, and interstitial fibrosis.

Conclusions:

• Idiopathic nephrotic syndrome is characterized by the dysregulation of genes crucial for maintaining glomerular endothelial health.
• Endothelial dysfunction and associated molecular changes contribute significantly to the pathogenesis and progression of INS.
• Targeting endothelial pathways may offer novel therapeutic strategies for managing INS.