Aluminum exposure induces nephrotoxicity via fibrosis and apoptosis through the TGF-ß1/Smads pathway in vivo and in vitro.

Aluminum (Al), the most common element in nature, can enter the body through various routes. Unfortunately, excessive accumulation of Al in the body can cause chronic toxicity. In this study, rats were randomly allocated to 4 groups and intraperitoneally injected with AlCl3 solution at 0, 5, 10, and 20 mg/(kg·d), respectively, for 4 weeks. The kidney function of rats and Al contents in the kidney were measured, and the pathological structural changes and apoptosis of the kidney were observed. Meanwhile, the expression of fibrosis- and apoptosis-related proteins was detected with western blot. For the in vitro assay, HK-2 cells were used to construct a model to evaluate the effects of Al exposure on cell viability, cell apoptosis, and the expression of fibrosis- and apoptosis-related proteins. Additionally, the TGF-ß1/Smads pathway was also altered in HK-2 cells, followed by the measurement of changes in apoptosis and fibrosis-related proteins. The results revealed that Al could accumulate in kidney tissues, then leading to histopathological changes and kidney function impairment, promoting renal tubular cell apoptosis and renal collagen fiber deposition, and also elevating the expression of TGF-ß1/Smads pathway-related proteins. In vitro experiments also exhibited that Al exposure increased apoptosis and the expression of fibrosis-related factors in HK-2 cells, accompanied by activation of the TGF-ß1/Smads pathway. Further modulation of the TGF-ß1/Smads pathway manifested that activation of the TGF-ß1/Smads pathway facilitated Al-induced apoptosis and fibrosis-related factor expression, while inhibition of the pathway negated this effect of Al. In conclusion, the findings of the present study illustrate that Al exposure damages kidney function and facilitate apoptosis and kidney fibrosis, which may be achieved through the activation of the TGF-ß1/Smads pathway. This study provides a new theoretical basis for the study of nephrotoxicity induced by excessive Al exposure.

Molecular Mechanism of Aluminum-Induced Oxidative Damage and Apoptosis in Rat Cardiomyocytes.

Aluminum exposure can mediate either acute toxicity or chronic toxicity. Aluminum exerts toxic effects on the cardiovascular system, but there are few studies on its related mechanisms. In this study, we investigated the molecular mechanism of aluminum-induced oxidative damage and apoptosis in rat cardiomyocytes. Thirty-two male Wistar rats were randomly divided into four groups, including the control group (GC), low-dose group of aluminum exposure (GL), medium-dose group (GM), and high-dose group (GH), with eight rats in each group. The GL, GM, and GH groups were given 5, 10, and 20 mg/(kg·d) of AlCl3 solution by intraperitoneal injection, and the GC group received intraperitoneal injection of the same volume of normal saline (2 ml/rat/day), 5 times a week for 28 days. At the end of the experiment, the levels of aluminum, malondialdehyde (MDA), plasma lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CKMB), and alpha-hydroxybutyrate dehydrogenase (HBDH) were measured. The pathological changes of myocardium were observed by H&E staining. The apoptosis of cardiomyocytes was detected by TUNEL staining, and the expression of apoptosis-related proteins was determined by western blot. The results showed that the levels of CKMB and HBDH in the GM and GH groups were significantly higher than those in the GC group (P < 0.05). The content of aluminum in the myocardium and serum of the aluminum exposure groups was significantly higher than that of the GC group (P < 0.05). The level of MDA in the GM and GH groups was significantly higher than that in the GC group (P < 0.05). The pathological results showed that vacuolated and hypertrophied cardiomyocytes were found in aluminum exposure groups, especially in the GM and GH groups. The TUNEL staining showed that the apoptosis rate of the aluminum exposure groups was considerably higher than that of the GC group (P < 0.05). Western blot showed that the expression of Bcl-2, an anti-apoptotic protein, in cardiomyocytes of aluminum exposure groups was lower than that of the GC group (P < 0.05), while the levels of Bax and caspase-3 in the cardiomyocytes of the GM and GH groups were higher than those of the GC group (P < 0.05). The experimental results showed that aluminum could accumulate in myocardial tissues and cause damage to cardiomyocytes. It could induce oxidative stress damage by increasing the content of MDA in cardiomyocytes and trigger cardiomyocyte apoptosis by activating the pro-apoptotic proteins caspase-3 and Bax and reducing the anti-apoptotic protein Bcl-2.

Effect of Aluminum Exposure on Glucose Metabolism and Its Mechanism in Rats.

The effects of aluminum (Al) exposure on glucose metabolism and its mechanism were investigated. A total of 30 healthy Wistar male rats were randomly divided into two groups: control (GC) and experimental (GE). The GC group received intraperitoneal normal saline. The GE was established by intraperitoneal injected AlCl3 solution at 10 mg/kg for 30 days. Fasting blood glucose (FBG) and serum levels of insulin (FINS) were measured. The insulin resistance index (HOMA-IR) and pancreatic ß cell function index (HOMA-ß) were calculated and analyzed with homeostasis model assessment (HOMA). Pancreatic tissue was taken for pathological examination. Glucose transporter 4 (GLUT4) expression in skeletal muscle was detected by quantitative PCR and Western blot. Levels of FBG and HOMA-IR in GE were higher than those in GC at day 10 and 20 (P < 0.05). FINS in GE were higher than those in GC at day 10 and 20, and lower than those in GC at day 30 (P < 0.05). HOMA-ß in GE was lower than that of GC at every time point (P < 0.05). Pathology showed that pancreatic damage changed more profoundly with prolongation of time in GE. Expression levels of GLUT4 mRNA and protein in rat skeletal muscle in GE were significantly lower than those in GC (P < 0.05). The results suggested that Al exposure affected glucose metabolism through pancreatic damage and reduction of GLUT4 expression.