Latest epidemiological data by the International Diabetes Federation (IDF) showed an estimated 463 million diabetes patients in 2019 worldwide, which would rise to 578 million by 2030 and 700 million by 2045 [1]. Diabetic kidney disease (DKD) is one of the most common microvascular complications in diabetes, and has become the leading cause of chronic and end-stage renal disease (ESRD), affecting approximately 40 % of the global diabetic population [2]. Due to the ever-increasing morbidity, mortality and considerable healthcare costs, it is important to understand the pathogenesis of DKD to guide development of more effective interventions.

Sodium-glucose cotransporter 2 (SGLT2) is expressed in proximal tubules and is essential for 80–90 % glucose reabsorption under physiological conditions [3]. SGLT2 inhibitors (SGLT2i) are relatively a noval class of oral glucose-lowering drugs, targeting renal proximal tubules to reduce glucose reabsorption, which results in glycosuria and anti-hyperglycemic effects [4]. Many previous clinical trials have demonstrated renal protective effects by SGLT2i, regardless of the status of diabetes 5., 6., 7., 8.. The SGLT2i have been recommended as first-line treatment options for type 2 diabetes patients with renal complications [9]. For instance, dapagliflozin is a first-in-class SGLT2i launched in 2012 with high selectivity and strong physiological effects [10]. Dapagliflozin has been shown to confer non-glycemic-related benefits, which include lowering blood pressure and body weight, as well as kidney protection 7., 11.. Although a growing number of studies have shown that SGLT2i exert renal protection via modulation of various pathological processes, such as insulin resistance, inflammation, fibrosis, oxidative stress and apoptosis 12., 13., the exact underlying mechanisms have not yet been elucidated.

High mobility group box 1 (HMGB1), a DNA-binding protein expressed in the nucleus, mediates many biological processes [14]. In diabetic rats, the HMGB1 protein is highly expressed in both cytoplasmic and nuclear regions of renal glomerular cells and tubular epithelial cells, and participates in the development of diabetic nephropathy through a RAGE-dependent pathway 15., 16.. Recently, Yao et al. demonstrated that dapagliflozin might attenuate high glucose induced inflammatory response and oxidative stress in human proximal tubular epithelial cells (HK-2) via inhibition of HMGB1-RAGE-NF-κB signaling pathway [17]. Therefore, it is feasible to speculate that HMGB1 might be mediating the renal protective effects of dapagliflozin in animal models of diabetes.

Here, we hypothesize that dapagliflozin attenuates nephropathy in diet-induced type 2 diabetes mice through inhibition of inflammation, oxidative and endoplasmic reticulum (ER) stress, mediated by suppression of renal HMGB1 expression and restoration of autophagy.