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Analysis of the SGLT2-independent off-target dapagliflozin activity using model organism Caenorhabditis elegans

ABSTRACT: Flozins, an emerging class of antidiabetic agents, selectively target the SGLT2 sodium/glucose cotransporter in the renal proximal tubule, thereby preventing glucose reabsorption and reducing hyperglycemia. Beyond their primary glucose-lowering mechanism, flozins exhibit significant benefits for heart failure and chronic kidney disease. This expanded therapeutic utility is noteworthy, particularly given the absence of SGLT2 expression in the cardiac tissue. Hereby we utilized Caenorhabditis elegans as a model organism to analyze flozin off-target activity, specifically by dapagliflozin treatment. Although C. elegans lacks direct SGLT2 orthologue, dapagliflozin remarkably mirrored observations in murine models, specifically demonstrating prolonged longevity in glucose-fed conditions. Furthermore, transcriptomic analysis of glucose- and dapagliflozin-treated worms, compared to glucose-only treated controls, revealed a gene expression profile reminiscent of mammalian systems. In line with this, we also observed that dapagliflozin inhibits glucose transport in C. elegans in vivo, as estimated using fluorescent glucose derivative 2-NBDG. Moreover, 2-NBDG transport inhibition by dapagliflozin was abrogated by downregulation of smvt-1 (sodium-dependent MultiVitamin Transporter) expression. This suggested that SMVT-1 is relevant dapagliflozin target in the worm.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE307680 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Purpose:Renal injury with the loss of podocyte was characteristic pathology of diabetic nephropathy (DN) and correlated with increased albuminuria. Many studies have found the nephroprotective effect of the novel inhibitors of sodium-glucose cotransporter 2 (SGLT2-is), like Dapagliflozin, delaying the progression of DN. However, the underlying mechanisms of SGLT2 associated with podocyte injury are still not fully elucidated. Methods: Through mRNA sequencing, streptozotocin-induced and Dapagliflozin-intraperitoneal injection mice models were established to explore potential mechanism between Dapagliflozin and renal phenotype. And all changes referring this observed pathway were proven repeatedly in podocyte. Results: Here, we generated the streptozotocin-induced DN models and found the accumulation of nephrotoxin and pathological lesions of the kidney, including interstitial inflammatory infiltration, mesangial expansion and glomerular sclerosis, while low expression of SGLT2 mitigated these injuries in Dapagliflozin-treated mice. Moreover, mRNA expression profile in these treated models determined the significance of insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. Particularly, SGLT2-is inhibited the increase of mesenchymal marker, α-SMA and the decrease of podocyte marker, nephrin at the gene or protein level. KEGG analysis also showed the enrichment of phosphatidylinositol signaling system and TGF-β/smad pathway. In parallel, the protein level of IGF1R, phosphorylated PI3K, and α-SMA were increased in high-glucose stimulated human podocyte, and reduced in Dapagliflozin (50nM and 100nM) or OSI-906 (inhibitor of IGF1R, 60nM) used groups. Notably, combination of the two inhibitors produced an accumulative effect in the protection of podocyte integrity. Mechanistically, IGF1 or IGF2 could bind to IGF1 receptors to mediate the epithelial-mesenchymal transition (EMT) of diabetic podocyte in response to the upregulation of SGLT2. Indeed, we enrolled the urine and plasma samples from a cohort consisting of 13 healthy people, and a cohort of 19 patients with DN using SGLT2-inhibitors (n=9) or not (n=10). Compared with pure DN patients, Elisa results suggested an increased circulation and excretion level of IGF1/2 in SGLT2-is used DN cohort. Conclusions: Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte EMT. Modulating the IGF1R expression may provide a novel idea for DN therapy.

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Analysis of the SGLT2-independent off-target dapagliflozin activity using model organism Caenorhabditis elegans

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