Attenuation of Hyperlipidemia- and Diabetes-Induced Early-Stage Apoptosis and Late-Stage Renal Dysfunction via Administration of Fibroblast Growth Factor-21 Is Associated with Suppression of Renal Inflammation

Abstract

BackgroundLipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions.ObjectiveThe present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism.MethodsMice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot.ResultsAcute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21.ConclusionThese results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.

Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study

“…In a recent animal study, FGF21 administration markedly decreased urinary albumin excretion and mesangial expansion and improved renal lipid metabolism and oxidative stress injury in db/db mice [31]. In another study, diabetes-and hyperlipidaemia-induced renal damage was enhanced in Fgf21-knockout mice, but was prevented by exogenous FGF21 administration [32]. These studies suggest that FGF21 may play a role in diabetic nephropathy through its effect on glucose and lipid metabolism.…”

Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

“…Moreover, Kim et al (27) demonstrated that FGF21 protects the kidneys in a mouse model of type 2 diabetes by improving insulin sensitivity. Our previous study (56) also demonstrated the beneficial effect of FGF21 on type 1 diabetes-induced renal damage.…”

“…A 180-kVp X-ray generator (Model XSZ-Z20/20, China) was used to deliver radiation at a dose rate of 12.5 mGy/min (120 kv, 13 mA). Diabetic mice in the DM/LDR and DM/Com groups received whole body irradiation every 2 days at a dose of 50 mGy/day for 4 wk, based on our previous observations (56). Mice in the DM/FGF21 or DM/Com groups were given intraperitoneal (ip) injections of 1.5 mg/kg FGF21 daily for 8 wk.…”

“…FGF21 might mainly suppress the systemic pathogenesis, whereas LDR might protect the kidneys from diabetes mainly via anti-inflammatory, antioxidative, and antifibrotic mechanisms (51,56,57). Therefore, the aim of the present study was to investigate whether the combination treatment with LDR and FGF21 could exert additive effects on the prevention of DN via both systemic and renal mechanisms.…”

Pharmacological Use of NLRP3 Inflammasome Inhibitors: Novel Intervention Strategies in Diabetes-Associated Vascular Complications

“…Yang et al [16] reported that thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via suppressing the NF-κB/NLRP3 inflammasome-mediated inflammatory process. Recently, Zhang et al [17] reported that FGF-21 can significantly prevent diabetes-induced early-stage renal apoptosis, hypertrophy, and dysfunction, and significant prevented inflammation, oxidative damage and fibrotic effect.…”