Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway.

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

The programming of kidney injury in offspring affected by maternal overweight and obesity: role of lipid accumulation, inflammation, oxidative stress, and fibrosis in the kidneys of offspring

Maternal overweight and obesity are considered important factors affecting fetal development with many potential consequences for offspring after delivery, including the increased risk of obesity and diabetes mellitus. Maternal obesity promotes adiposity in the offspring by increasing fat deposition and expansion in the body of the offspring. The expansion of adipose tissue changes adipokine levels, including a decrease in adiponectin and an increase in leptin. In addition to changes in adipokine levels, there are also increases in pro-inflammatory cytokines, pro-fibrotic cytokines, and reactive oxygen species, leading to oxidative stress in the offspring. These contribute to the promotion of insulin resistance in offspring, which is associated with kidney injury. Interestingly, maternal obesity can also promote renal lipid accumulation, which could activate inflammatory processes and promote renal oxidative stress and renal fibrosis. These alterations in the kidneys of the offspring imply that a mother being overweight/obese can program the development of kidney disease in offspring. This review will discuss the effects of a mother being overweight or obese on their offspring and the consequences with regard to the kidneys of their offspring. With a focus on the molecular mechanisms, including renal inflammation, renal oxidative stress, renal fibrosis, and renal lipid metabolism in offspring born to overweight and obese mothers, the causative mechanisms and perspective of these conditions will be included. (AU)

Resistant starch from black rice, Oryza sativa L. var. ameliorates renal inflammation, fibrosis and injury in insulin resistant rats.

It has recently been reported that black rice (BR) extract has anti-obesity, anti-diabetic, and anti-osteoporosis effects. It has been shown to reduce obese-related kidney dysfunction in animal models. This study aimed to investigate the effect of resistant starch from BR (RS) on renal inflammation, oxidative stress, and apoptosis in obese insulin resistant rats. Male Wistar rats were divided into six groups: normal diet (ND), ND treated with 150 mg of RS (NDRS150), high-fat (HF) diet, HF treated with 100 and 150 mg of RS (HFRS100), (HFRS150), and HF treated with metformin as a positive control. Insulin resistance was shown in the HF rats by glucose intolerance, increased insulin, total area under the curve of glucose and homeostasis model assessment of insulin resistance and dyslipidemia. The resulting metabolic disturbance in the HF rats caused renal inflammation, fibrosis and apoptosis progressing to kidney injury and dysfunction. Prebiotic RS including anthocyanin from BR at doses of 100 and 150 mg ameliorated insulin resistance, dyslipidemia and liver injury. Treatment with RS reduced TGF-ß fibrotic and apoptotic pathways by inhibition of NF-κB and inflammatory cytokines which potentially restore kidney damage and dysfunction. In conclusion, prebiotic RS from BR ameliorated obesity induced renal injury and dysfunction by attenuating inflammatory, fibrotic, and apoptotic pathways in insulin resistant rats induced by HF.

The programming of kidney injury in offspring affected by maternal overweight and obesity: role of lipid accumulation, inflammation, oxidative stress, and fibrosis in the kidneys of offspring.

Maternal overweight and obesity are considered important factors affecting fetal development with many potential consequences for offspring after delivery, including the increased risk of obesity and diabetes mellitus. Maternal obesity promotes adiposity in the offspring by increasing fat deposition and expansion in the body of the offspring. The expansion of adipose tissue changes adipokine levels, including a decrease in adiponectin and an increase in leptin. In addition to changes in adipokine levels, there are also increases in pro-inflammatory cytokines, pro-fibrotic cytokines, and reactive oxygen species, leading to oxidative stress in the offspring. These contribute to the promotion of insulin resistance in offspring, which is associated with kidney injury. Interestingly, maternal obesity can also promote renal lipid accumulation, which could activate inflammatory processes and promote renal oxidative stress and renal fibrosis. These alterations in the kidneys of the offspring imply that a mother being overweight/obese can program the development of kidney disease in offspring. This review will discuss the effects of a mother being overweight or obese on their offspring and the consequences with regard to the kidneys of their offspring. With a focus on the molecular mechanisms, including renal inflammation, renal oxidative stress, renal fibrosis, and renal lipid metabolism in offspring born to overweight and obese mothers, the causative mechanisms and perspective of these conditions will be included.

Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats.

This study aimed to investigate the renoprotective effect of agomelatine on kidney injury in an obese rat model and to understand the underlying mechanisms involving the AMPK-mTOR-autophagy signaling pathway. Male Wistar rats were fed either a normal (ND) or a high-fat diet (HF) for 16 weeks. The HF rats were divided into 4 groups: (1) HF control; (2) AGOM20 receiving agomelatine 20 mg. kg-1 day-1; (3) AGOM40 receiving agomelatine 40 mg. kg-1 day-1; and (4) NAC receiving N-acetylcysteine 100 mg. kg-1 day-1 by oral gavage for 4 weeks. HF rats demonstrated insulin resistance, impaired renal function and oxidative stress as evidenced by the elevation of MDA levels and expression of PKCα and NOX4. These alterations correlated with impaired autophagy, renal fibrosis and apoptosis. Agomelatine showed a greater efficacy than NAC treatment with regard to improving insulin resistance, dyslipidemia and renal dysfunction through alleviation of oxidative stress, fibrosis and apoptosis in kidney cells. Impaired autophagy was blunted after agomelatine or NAC administration, as demonstrated by the increased in Beclin-1, LC3B, Atg5, LAMP2, and AMPK, and decreased mTOR and CTSB expression. These data revealed that agomelatine protected against obesity-induced kidney injury via the regulation of ROS and AMPK-mTOR-autophagy signaling pathways.

Chitosan oligosaccharide mitigates kidney injury in prediabetic rats by improving intestinal barrier and renal autophagy.

Consumption of a high-fat diet (HFD) not only increases the risk of metabolic syndrome but also initiates kidney injury. Lipid accumulation-induced systemic low-grade inflammation is an upstream mechanism of kidney injury associated with prediabetes. Chitosan oligosaccharide (COS) provides potent anti-obesity effects through several mechanisms including fecal lipid excretion. In this study, we investigated the effects of COS on the prevention of obesity-related complications and its ability to confer renoprotection in a prediabetic model. Rats fed on a HFD developed obesity, glucose intolerance and kidney dysfunction. COS intervention successfully ameliorated these conditions (p < 0.05) by attenuating intestinal lipid absorption and the renal inflammation-autophagy-apoptosis axis. A novel anti-inflammatory effect of COS had been demonstrated by the strengthening of intestinal barrier integrity via calcium-sensing receptor (p < 0.05). The use of COS as a supplement may be useful in reducing prediabetic complications especially renal injury and the risk of type 2 diabetes.

The combination of dapagliflozin and statins ameliorates renal injury through attenuating the activation of inflammasome-mediated autophagy in insulin-resistant rats.

Long-term use of a high-fat diet with high-fructose (HFF) intake could promote insulin resistance and induce lipid accumulation leading to kidney injury possibly via impairment of the autophagy process and enhancement of the inflammasome pathway. We investigated whether dapagliflozin as a monotherapy or combined with atorvastatin could restore kidney autophagy impairment and reduce inflammasome activation associated with kidney injury induced by HFF consumption. Male Wistar rats were given an HFF for 16 weeks and then treated with dapagliflozin with or without atorvastatin for 4 weeks. Impaired glucose tolerance, dyslipidemia, renal lipid accumulation along with impaired renal autophagy and activated inflammasome pathway promoted renal injury were exhibited in HFF rats. Dapagliflozin with or without atorvastatin treatment could partially restore disrupted metabolic parameters and reduce kidney injury. In particular, the combination treatment group showed significant amelioration of inflammasome activation and autophagy impairment. In conclusion, the combination therapy of dapagliflozin and atorvastatin has a positive effect on renal injury associated with autophagy and inflammasome activation induced by HFF in insulin-resistant rats. This study is the first report demonstrating the underlying mechanism associated with a combination treatment of dapagliflozin and atorvastatin on autophagy and inflammasome pathways in an insulin-resistant condition. Therefore, dapagliflozin in combination with atorvastatin may be a further preventive or therapeutic strategy for chronic kidney disease in an insulin-resistant or diabetic condition.

Agomelatine protects against obesity-induced renal injury by inhibiting endoplasmic reticulum stress/apoptosis pathway in rats.

Obesity is recognized as a risk for the development of chronic kidney disease. Excessive fat accumulation in obesity is associated with the overproduction of reactive oxygen species with the underproduction of antioxidant mechanisms generating oxidative stress together with chronic low-grade inflammation which subsequently leads to the development of several obesity-related complications. It has been suggested that the abnormal lipid accumulation can induce endoplasmic reticulum (ER) stress and cellular apoptosis in several tissue types. Agomelatine is a relatively new antidepressant which is a synthetic agonist of melatonin. Previous study reported the antioxidant and anti-inflammatory effects of agomelatine. In this study, we investigated the therapeutic effects of agomelatine in obesity-related renal injury. Male Wistar rats were fed with normal diet or high-fat diet (HF) for 16 weeks. After that, vehicle or agomelatine or vildagliptin was orally administered to HF rats for 4 weeks. Our results indicated that HF rats demonstrated insulin resistance which was accompanied by an impairment of renal function and renal organic anion transporter 3 (Oat3) function as well as renal oxidative stress, ER stress, and apoptosis. Interestingly, agomelatine treatment not only improved the metabolic parameters, renal function and renal Oat3 function but also attenuated renal oxidative stress, ER stress and subsequent apoptosis. Therefore, agomelatine exerted renoprotective effects in obese insulin-resistant condition. These results suggested that agomelatine could be used as a drug to improve metabolic disturbance and prevent kidney dysfunction in obese condition.