Multi-Omic Profiling Defines the Renal Mechanisms of Cardiovascular-Kidney-Metabolic Syndrome in Pulmonary Arterial Hypertension
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Background
Cardiovascular-kidney-metabolic (CKM) syndrome integrates cardiac, renal, and metabolic abnormalities that drive multi-organ injury. In pulmonary arterial hypertension (PAH), CKM manifests as systemic metabolic derangements, right ventricular dysfunction, and renal compromise. Renal dysfunction strongly predicts mortality in PAH, yet current therapies provide little renal benefit. Moreover, the mechanisms driving PAH nephropathy remain poorly understood, limiting our ability to effectively treat PAH-CKM.
Methods
Single-nucleus RNAsequencing identified cell-type-specific transcriptional alterations in autopsy-derived kidneys from control (n=5) and PAH (n=4) patients. Mitochondrial, cytoplasmic, and phosphoproteomic analyses profiled proteomic alterations. AlphaFold 3/ChimeraX modeling defined the predicted structural consequences of altered protein phosphorylation. Histological analysis assessed renal fibrosis, glomerular structure, immune cell infiltration, and nephron segment density.
Results
3 of 4 PAH patients exhibited renal impairment, with a cohort mean estimated glomerular filtration rate of 61±36 mL/min/1.73m². snRNA-seq identified a distinct cellular architecture in PAH kidneys, marked by an increase in thick ascending limb, proximal tubule, and immune cell nuclei and depletion of collecting duct nuclei. Transcriptional profiling demonstrated proximal tubule and thick ascending limb cells both upregulated fatty acid oxidation, ferroptosis, and cuproptosis pathways. PAH lymphocytes displayed heightened T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and Th17 differentiation. Histological analyses demonstrated increased perivascular fibrosis, glomerular T-cell infiltration, and a reduction in glomerular basement membrane density in PAH kidneys. Mitochondrial and cytoplasmic proteomics revealed broad metabolic dysfunction characterized by impaired β-oxidation, TCA cycle activity, amino acid metabolism, transsulfuration, and urea cycle pathways. Phosphoproteomics predicted increased GSK3β, STK, and casein kinase activity in PAH kidneys. Finally, using the totality of our data, we nominated multiple druggable targets that could be evaluated to counteract PAH nephropathy.
Conclusions
Integrated multi-omic profiling demonstrates PAH nephropathy is defined by glomerular structural remodeling, proximal nephron ferroptotic and cuproptotic signaling, amino acid metabolic dysregulation, and innate and adaptive leukocyte activation. Future studies intervening on these pathways could lead to the development of novel therapeutics to augment renal function in PAH.
Clinical Perspective
What Is New?
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Single-nucleus RNA sequencing and histological analyses defined nephron remodeling and increased leukocyte infiltration as key cellular features of the PAH kidney.
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Integrated transcriptomic and proteomic analyses nominated metabolic derangements including ferroptosis, cuproptosis, disrupted fatty acid and amino acid metabolism, and impaired TCA cycle activity as candidate drivers of PAH nephropathy.
What Are the Clinical Implications?
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Discrete cellular and metabolic mechanisms may contribute to PAH-CKM syndrome, which suggests renal dysfunction is not solely due to abnormal hemodynamics.
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Dysregulated programmed cell death pathways, immune signaling, amino acid metabolism, and kinase activity may be potentially druggable targets that could be engaged to counteract PAH-CKM.
