Introduction  Chronic kidney disease (CKD) 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. We hypothesize that SOTA recovers the maladaptive cardiac gene profile in cardiorenal HFpEF, offering insight into its cardioprotective effects.

Methods  CKD was surgically induced in male Wistar rats (n=15) using 5/6 nephrectomy for a period of 4 weeks, with SOTA treatment (5mg/kg/day) administered for 3 weeks. Bulk RNA sequencing was performed on cardiac tissue harvested at experimental endpoint. Differential gene expression analysis was carried out in RStudio v4.4.2 using DESeq2. 

Results  Our previous work shows 3-week SOTA treatment improves the cardiometabolic profile in CKD1.  Exploratory differential gene expression analysis was conducted (Log2FC±0.25,p.adj<0.1). Differentially expressed genes (DEGs) were identified in CKD vs Sham (n=4), CKD vs Sota (n=24), and Sham vs Sota (n=36) comparisons. No overlapping DEGs were found across comparisons, indicating distinct cardiac genetic profiles across all groups. Of note, Tnfrsf11b (OPG) was upregulated in CKD vs Sham, a gene associated with vascular calcification, bone remodelling and adverse cardiac outcomes. Whilst SOTA treatment reduced expression of S100a8, a gene associated with inflammation and fibrosis, compared to untreated CKD. The role of several significant DEGs identified in CKD and SOTA groups is not yet known in CKD-HFpEF. The DEGs identified between Sham and Sota groups showed low Log2FC changes indicating a rescue of CKD-induced cardiac remodelling.  Conclusion We find that SOTA treatment improves cardiometabolic dysfunction in CKD potentially due to induction of a distinct genetic profile.