Nephron-associated Support Cell Transcriptional Plasticity Expands in Hypertension

Area of Science:

• Nephrology
• Immunology
• Regenerative Medicine

Background:

• Hypertension (HTN) affects over one billion people globally, leading to severe cardiovascular and renal complications.
• Kidney cell death and subsequent inflammation are primary consequences of sustained high blood pressure.
• Certain cell types possess immunomodulatory and regenerative capabilities, showing promise for treating HTN and kidney disorders.

Purpose of the Study:

• To investigate the characteristics and therapeutic potential of multipotent nephron-associated support cells (SCs) in the context of hypertension-induced kidney damage.
• To compare the molecular profiles and inflammatory responses of SCs and lymphatic endothelial cells (LECs) in hypertensive mouse models.

Main Methods:

• Single-cell RNA sequencing was employed to analyze CD31+ and podoplanin+ cells from the kidneys of hypertensive and control mice.
• Differential gene expression, pathway enrichment analysis (MSigDB M2 and M5), and regulon analysis were performed.
• Comparative analysis between SCs and LECs under hypertensive conditions was conducted.

Main Results:

• Hypertension-induced SCs exhibited 299 differentially expressed genes and enriched pathways, along with 180 HTN-specific regulons.
• Comparison with LECs revealed significant differences in gene expression (3636 genes) and pathway enrichment (M2: 537, M5: 415) in HTN samples.
• SCs from hypertensive mice demonstrated greater resistance to inflammation-induced changes than LECs, downregulating stem cell suppressive genes and upregulating regenerative genes.

Conclusions:

• Nephron-associated support cells in hypertensive kidneys possess inherent resistance to inflammation and exhibit a pro-regenerative molecular signature.
• These findings highlight SCs as a potential cell-based therapy for mitigating hypertension-related kidney damage and promoting renal repair.