Transient inhibition of sodium-glucose cotransporter 2 after ischemia/reperfusion injury ameliorates chronic kidney disease

Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly a...

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Published in:JCI insight 2024-02, Vol.9 (6)
Main Authors: Martínez-Rojas, Miguel Ángel, Balcázar, Hiram, González-Soria, Isaac, González-Rivera, Jesús Manuel, Rodríguez-Vergara, Mauricio E, Velazquez-Villegas, Laura A, León-Contreras, Juan Carlos, Pérez-Villalva, Rosalba, Correa, Francisco, Rosetti, Florencia, Bobadilla, Norma A
Format: Article
Language:English
Subjects:
Acute Kidney Injury - drug therapy
Acute Kidney Injury - metabolism
Acute Kidney Injury - prevention & control
Animals
Benzhydryl Compounds - pharmacology
Benzhydryl Compounds - therapeutic use
Glucose
Humans
Male
Rats
Rats, Wistar
Renal Insufficiency, Chronic - drug therapy
Reperfusion Injury - complications
Reperfusion Injury - metabolism
Sodium - metabolism
Sodium-Glucose Transporter 2 - drug effects
Sodium-Glucose Transporter 2 Inhibitors - pharmacology
Sodium-Glucose Transporter 2 Inhibitors - therapeutic use
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Summary:Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly assigned to Sham surgery, bilateral ischemia for 30 minutes (abbreviated as IR), and IR + Dapa groups. Daily treatment with Dapa was initiated just 24 hours after IR and maintained for only 10 days. Initially, rats were euthanized at this point to study early renal repair. After severe AKI, Dapa promptly restored creatinine clearance (CrCl) and significantly reduced renal vascular resistance compared with the IR group. Furthermore, Dapa effectively reversed the mitochondrial abnormalities, including increased fission, altered mitophagy, metabolic dysfunction, and proapoptotic signaling. To study this earlier, another set of rats was studied just 5 days after AKI. Despite persistent renal dysfunction, our data reveal a degree of mitochondrial protection. Remarkably, a 10-day treatment with Dapa demonstrated effectiveness in preventing CKD transition in an independent cohort monitored for 5 months after AKI. This was evidenced by improvements in proteinuria, CrCl, glomerulosclerosis, and fibrosis. Our findings underscore the potential of Dapa in preventing maladaptive repair following AKI, emphasizing the crucial role of early intervention in mitigating AKI long-term consequences.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.173675