Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Impact of dual SGLT1/2 inhibitor Sotagliflozin on the cardiac genetic profile in cardiorenal heart failure with preserved ejection fraction (HFpEF)

ABSTRACT: Chronic kidney disease (CKD), affecting over 800million individuals globally, causes a distinct cardiorenal HFpEF phenotype, characterised by metabolic, structural and functional remodelling. Sotagliflozin (SOTA), a dual sodium-glucose co-transporter (SGLT) 1 and 2 inhibitor, has demonstrated superior efficacy in reducing cardiovascular events in CKD patients. This study investigates impact of SOTA treatment on cardiac genomic profile in CKD. The study included three groups (n = 5 per group): Sham, CKD, and SOTA-treated CKD. CKD was surgically induced in male Wistar rats (n = 10) using 5/6 nephrectomy for a period of 4 weeks, with SOTA treatment (5 mg/kg/day) administered for 3 weeks. Bulk RNA sequencing was performed on cardiac tissue harvested at experimental endpoint.

INSTRUMENT(S): DNBSEQ-G400

ORGANISM(S): Rattus norvegicus

SUBMITTER: Sanushi Dambure

PROVIDER: E-MTAB-16042 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Cardiovascular disease (CVD) causes more than 50% of deaths in patients with advanced chronic kidney disease (CKD). CVD degree correlates with CKD severity. Clinical studies suggest that kidney-derived factors contribute to the development of CVD in CKD, independently of co-morbidities like hypertension and hyperglycemia. However, to date, no kidney-specific humoral risk factor that triggers direct cardiotoxicity has yet been identified, primarily due to the paucity of studies in patients with reno-cardiac disease. Here, we investigate how, in CKD patients, circulating extracellular vesicles (EVs) facilitate pathological kidney-heart communication, thereby causing cardiotoxicity, impairing cardiac function and contributing to heart failure (HF) progression. Methods and results: EVs isolated from the plasma of patients with CKD (hCKD-EVs), but not healthy controls (hCtr-EVs), were cardiotoxic, significantly inducing apoptosis both in vitro and in vivo and impairing contractility of isolated adult rat primary CMs in vitro. Likewise, EVs isolated from both plasma and kidneys of adenine diet-induced CKD mice were also cardiotoxic. Pharmacologically depleting circulating EVs in CKD mice significantly recovered cardiac function and ameliorated HF, suggesting CKD-EVs play a causal role in HF pathogenesis. Small RNA sequencing and q-RT-PCR validation uncovered distinct miRNAs enriched in both human and mouse CKD-EVs, compared to Ctr-EVs. CKD-EV-miRNA mimics were cardiotoxic to human ventricular AC16 myocytes inducing apoptosis and to iPSC-derived cardiomyocytes, impairing contractility and downregulating contractile gene expression. Interestingly, levels of endogenous primary miRNAs corresponding to CKD-EV-miRNAs were significantly higher in CKD-kidney tissues, specifically in CD45-veCD31-ve renal cells, but not in CKD-livers, CKD-lungs or CKD-PBMCs from peripheral blood, a result that suggests that CKD-EV-miRNAs originate renally. Remarkably, CKD-EV-miRNA levels correlated with established markers of cardiac injury, uncovering the presence of sub-clinical heart disease and demonstrating heterogeneity in CKD patients not yet diagnosed with HF. Conclusion: Collectively, our human subject and mouse studies show that circulating CKD-EVs, carrying distinct renal-derived miRNAs, mediate the molecular crosstalk that contributes to the pathogenesis of HF in CKD. Consequently, CKD-EVs hold promise as diagnostic and prognostic biomarkers for early disease detection and as targets for novel therapeutic interventions in chronic reno-cardiac disease.

Dataset Information

Impact of dual SGLT1/2 inhibitor Sotagliflozin on the cardiac genetic profile in cardiorenal heart failure with preserved ejection fraction (HFpEF)

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