Hinokitiol prevents diabetic acute kidney injury by mitigating er stress

Abstract

Acute kidney injury (AKI) in diabetic conditions often advances to chronic kidney disease (CKD), exacerbated by ischemia–reperfusion injury (IRI) through pathomechanisms such as endoplasmic reticulum (ER) stress and inflammation. Currently, available treatment options for diabetic AKI are not uniformly effective, highlighting the need for novel interventions. This study aimed to examine the renoprotective effects of hinokitiol, a natural tropolone compound, against diabetic AKI with its capability to decrease ER stress and inflammation, along with apoptosis. This study involved NRK-52E cells grown in-vitro under high-glucose conditions subjected to 10 mM sodium azide to elicit hypoxia/reperfusion injury (HRI). The expression of key ER stress markers like binding immunoglobulin binding protein (BiP), R/PKR-like ER kinase (PERK), and eukaryotic initiation factor-2 (eIF2α) as well as inflammatory proteins was markedly diminished by hinokitiol pretreatment (50 μM). Hinokitiol further reduced apoptosis in the NRK-52E cells. Similarly, in the in-vivo study, male Wistar rats with STZ-induced Type 1 diabetes (55 mg/kg, i.p.) were treated with hinokitiol 50 and 100 mg/kg/day i.p. for 5 days, followed by AKI induction via bilateral IRI. Hinokitiol pretreatment significantly reduced the elevated plasma blood urea nitrogen (BUN), creatinine, and urinary kidney injury molecule-1 (KIM-1) levels and tubular damage in diabetic AKI rats. Hinokitiol also reduced the respective ER stress protein expressions in diabetic AKI rats, as demonstrated by immunohistochemical analysis and immunoblotting. These findings suggest that hinokitiol alleviates diabetic AKI by modulating the PERK/CHOP/NF-κB axis, highlighting the likeliness of hinokitiol as a viable therapeutic technique for alleviating diabetic AKI.