Chronic RAAS Suppression Drives Hypoxic Metabolic Reprogramming and Vascular Remodeling in the Kidney

Included here are the steps to analyze and product figures related to sequencing data from "Chronic RAAS Suppression Drives Hypoxic Metabolic Reprogramming and Vascular Remodeling in the Kidney".

Chronic inhibition of the renin-angiotensin-aldosterone system (RAAS), a cornerstone of antihypertensive therapy, drives concentric arterial and arteriolar hypertrophy (CAAH), a progressive renal vascular disease whose molecular and metabolic basis remained undefined. Structural injury precedes detectable kidney function decline, creating a window during which disease advances silently. Three-dimensional vascular imaging reveals the extent of this remodeling, with luminal narrowing spanning the renal arterial tree. In mouse models of genetic and pharmacologic RAAS suppression, fate-mapping shows that renin cells and their smooth muscle descendants adopt inflammatory, fibrotic, and secretory states accompanying progressive vessel wall thickening. Integrating single-cell transcriptomics, proteomics, and metabolomics, we identify a conserved hypoxia-associated metabolic program marked by glycolytic shift and impaired mitochondrial function. This analysis also yields a 10-gene molecular signature of CAAH validated in independent human kidney disease cohorts. Candidate urinary biomarkers establish a framework for non-invasive detection of this incompletely understood vascular pathology.

Requirements

Operating system: Linux x86-64

Estimated runtime: approximately 48-72 hours end-to-end (raw data processing through figure generation)

Key software:

The complete reproducible environment specification (conda environment.yml) is in Create Analysis Environment.