Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is the primary genetic cause of end-stage renal disease.
• ADPKD is characterized by the progressive development of kidney cysts.

Purpose of the Study:

• To elucidate the specific cell types and cellular states contributing to ADPKD progression.
• To create a comprehensive single-cell multiomic atlas of human ADPKD kidneys.

Main Methods:

• Analysis of eight ADPKD and five healthy human kidney samples.
• Generation of a single-cell multiomic atlas including transcriptomes and epigenomes.
• Identification and validation of gene regulatory elements.

Main Results:

• Proximinal tubular cells with failed repair signatures, proinflammatory fibroblasts, and collecting duct cells drive inflammatory and fibrotic pathways.
• GPRC5A identified as a marker for cyst-lining collecting duct cells.
• NF-κB, TEAD, CREB, and retinoic acid receptor motifs are enriched in the regulatory regions of GPRC5A.

Conclusions:

• Single-cell multiomic analysis reveals significant cellular heterogeneity in ADPKD.
• Identified cellular drivers and regulatory mechanisms provide a foundation for developing novel diagnostic and therapeutic strategies for ADPKD.