Genomics and Multi-Omics Perspectives on the Pathogenesis of Cardiorenal Syndrome

Figures

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  Figure 1. Acute CRS (Type 1): Cardiac Arrest and Resuscitation Model. Mouse models of cardiac arrest and resuscitation have been used to study acute cardiorenal syndrome (CRS), where abrupt heart failure leads to acute kidney injury (AKI). Single-nucleus RNA sequencing (RNA-seq) of the kidney reveals significant transcriptomic changes, especially in proximal tubules (PT, segments S1/S2) and distal convoluted tubules (DCT), which exhibit loss of identity gene expression and dedifferentiation stress. Importantly, the renal transcriptomic profile after cardiac arrest-induced AKI closely mirrors that of human AKI biopsy samples, underscoring translational relevance. Gene enrichment analyses also implicate immune-inflammatory pathways, with both overlaps and distinctions compared to ischemia–reperfusion injury. Abbreviations: CRS, cardiorenal syndrome; AKI, acute kidney injury; PT, proximal tubule; S1/S2, proximal tubule segments; DCT, distal convoluted tubule; RNA-seq, RNA sequencing; Kidney snRNA-seq after cardiac arrest/resuscitation (GEO: GSE271437).

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  Figure 2. Chronic CRS (Type 2): Heart Failure-Driven Renal Proteome Remodeling. In a rat model of chronic heart failure induced by volume overload (aorto-caval fistula), quantitative proteomics identified 67 differentially expressed renal proteins despite near-normal renal function. Among the most upregulated were angiotensin-converting enzyme (ACE, >20-fold increase) and intrarenal angiotensin II (AT II, >5-fold increase), indicating strong activation of the renin–angiotensin system. Periostin (POSTN), a matricellular protein linked to fibrosis, and the receptor for advanced glycation end-products (RAGE) were also markedly elevated. These findings highlight that subclinical renal injury in chronic CRS is driven by early fibrotic and pro-inflammatory pathways. Abbreviations: CRS, cardiorenal syndrome; ACE, angiotensin-converting enzyme; AT II, angiotensin II; POSTN, periostin; RAGE, receptor for advanced glycation end-products; Renal proteomics in rat ACF model (PRIDE: PXD009296).

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  Figure 3. Cardiorenal Syndrome Type 4: Kidney Injury Induces Cardiac Remodeling. Unilateral ureteral obstruction (UUO) in mice, used to model early chronic kidney disease (CKD), triggers cardiac remodeling even in the absence of severe uremia. After 3 weeks, hearts show collagen deposition and increased α-smooth muscle actin (ACTA2), with RNA sequencing revealing 76 differentially expressed genes enriched in inflammatory, proliferative, and apoptotic pathways while suppressing mitochondrial metabolism. Larger animal studies corroborate these findings, demonstrating that renal injury drives myocardial transcriptomic reprogramming and progressive CRS within the broader CRS spectrum. Abbreviations: UUO, unilateral ureteral obstruction; CKD, chronic kidney disease; CRS, cardiorenal syndrome; ACTA2, actin alpha 2 (smooth muscle actin); Cardiac RNA-seq in UUO mice (GEO: GSE235751).

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  Figure 4. Fibrotic Pathways as a Cornerstone of CRS. Multi-omics studies consistently implicate fibrosis and extracellular matrix (ECM) remodeling as central pathways in CRS pathogenesis. Differentially expressed genes and proteins include fibronectin-1 (FN1), periostin (POSTN), collagens, and cytoskeletal proteins such as vimentin, alongside signaling mediators in the transforming growth factor-β (TGF-β) pathway. Matrix metalloproteinases (MMPs) and related protease inhibitors reflect active ECM turnover and remodeling. Biomarkers of collagen degradation (e.g., urinary fragments, circulating procollagen peptides) may enable early detection of CRS prior to functional decline. Therapeutic targeting of fibrosis through anti-fibrotic drugs, anti-TGF-β strategies, and microRNA modulation is a promising translational direction. Abbreviations: FN1, fibronectin-1; POSTN, periostin; TGFβ, transforming growth factor beta; ECM, extracellular matrix; MMP, matrix metalloproteinase; PRIDE accessions listed in Table S1).

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  Figure 5. Inflammation, Oxidative Stress, and RAAS Hyperactivation in CRS. Inflammatory and immune pathways are strongly upregulated in CRS, with transcriptomic profiles showing cytokine release, macrophage recruitment, leukocyte trafficking, and complement cascade activation. Oxidative stress markers such as myeloperoxidase and NADPH oxidase components further damage cardiac and renal tissue. Parallel proteomic studies demonstrate marked activation of RAAS, with renal ACE levels >20-fold higher and angiotensin II massively elevated, promoting vasoconstriction, fibrosis, and inflammatory signaling through AT1 receptors. Aldosterone excess exacerbates myocardial fibrosis and renal injury. These pathways intersect, as angiotensin II can stimulate TGFβ and ROS production, linking neurohormonal, inflammatory, and fibrotic mechanisms in CRS progression. Abbreviations: CRS, cardiorenal syndrome; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system; IL-6, interleukin-6; IL-1, interleukin-1; MCP-1, monocyte chemoattractant protein-1; TNFα, tumor necrosis factor alpha; ROS, reactive oxygen species; ATP, adenosine triphosphate;FN1, fibronectin-1; POSTN, periostin; SERPINE1,…

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  Figure 6. Mechanistic role of miR-21 in fibrosis. miR-21 is upregulated in cardiac and renal injury and represses PPAR-α, a metabolic and anti-fibrotic regulator. Loss of PPAR-α removes inhibitory control over oxidative stress and TGF-β signaling. In parallel, miR-21 suppresses SMAD7, thereby enhancing TGF-β/SMAD2/3/4 signaling. This cascade drives fibroblast activation, myofibroblast transition, extracellular matrix deposition, and progressive fibrosis. Antisense oligonucleotide therapy against miR-21 (e.g., lademirsen) has shown efficacy in preclinical models of kidney and heart fibrosis, although early clinical trials revealed limited benefit, underscoring the complexity of targeting a single microRNA in CRS. Abbreviations: PPAR-α, peroxisome proliferator-activated receptor-α; TGF-β, transforming growth factor-β; SMAD, homologs of Drosophila mothers against decapentaplegic; ECM, extracellular matrix; CRS, cardiorenal syndrome.