Acute Kidney Injury Sensitizes the Brain Vasculature to Ang II (Angiotensin II) Constriction via FGFBP1 (Fibroblast Growth Factor Binding Protein 1)
Authors: Zhao, Liang; Cao, Xiaoyun; Li, Lingli; Wang, Xiaohua; Wang, Qin; Jiang, Shan; Tang, Chun; Zhou, Suhan; Xu, Nan; Cui, Yu; Hu, Weipeng; Fei, Lingyan; Zheng, Zhihua; Chen, Limeng; Schmidt, Marcel O.; Wei, Qichun; Zhao, Jingwei; Labes, Robert; Patzak, Andreas; Wilcox, Christopher S.; Fu, Xiaodong; Wellstein, Anton; Lai, En Yin
Acute kidney injury (AKI) causes multiple organ dysfunction. Here, we identify a possible mechanism that can drive brain vessel injury after AKI. We induced 30-minute bilateral renal ischemia-reperfusion injury in C57Bl/6 mice and isolated brain microvessels and macrovessels 24 hours or 1 week later to test their responses to vasoconstrictors and found that after AKI brain vessels were sensitized to Ang II (angiotensin II). Upregulation of FGF2 (fibroblast growth factor 2) and FGFBP1 (FGF binding protein 1) expression in both serum and kidney tissue after AKI suggested a potential contribution to the vascular sensitization. Administration of FGF2 and FGFBP1 proteins to isolated healthy brain vessels mimicked the sensitization to Ang II after AKI. Brain vessels in Fgfbp1(-/-) AKI mice failed to induce Ang II sensitization. Complementary to this, systemic treatment with the clinically used FGF receptor kinase inhibitor BGJ398 (Infigratinib) reversed the AKI-induced brain vascular sensitization to Ang II. All these findings lead to the conclusion that FGFBP1 is especially necessary for AKI-mediated brain vascular sensitization to Ang II and inhibitors of FGFR pathway may be beneficial in preventing AKI-induced brain vessel injury.
Changes in Serum Levels and Gene Expression of PGC-1 alpha in The Cardiac Muscle of Diabetic Rats: The Effect of Dichloroacetate and Endurance Training
Authors: Nasab, Hamed Rezaei; Habibi, Abdol Hamid; Nikbakht, Masoud; Rashno, Mohammad; Shakerian, Saeed
Objective: Physical activity leads to changes in the level of gene expression in different kinds of cells, including changes in mitochondrial biogenesis in the myocardium in diabetic patients. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a gene that plays an important role in regulating mitochondrial biogenesis. The purpose of this study was to investigate changes in serum levels and cardiac muscle expression of PGC-1 alpha in diabetic rats in response to the administration of dichloroacetate (DCA) and endurance training. Materials and Methods: In this experimental study, 64 male Wistar rats were selected and randomly divided into eight groups after induction of diabetes with streptozotocin (STZ). The endurance training protocol was performed on a treadmill for 6 weeks. Intraperitoneal injection of DCA of 50 mg/kg body weight was used for the inhibition of Pyruvate Dehydrogenase Kinase 4 (PDK4) in the myocardium. Gene expression were measured using real-time polymerase chain reaction (PCR). One-way ANOVA and Tukey's test were used to statistically analyze the data. Results: The results of the study showed that PDK4 gene expression in the endurance training group, diabetes+endurance training group, diabetes+endurance training+DCA group and endurance training+DCA group was higher compared to the control group. Expression of PGC-1 alpha was higher in the endurance training group compared to the control group but was lower compared to the control group in diabetes+endurance training+DCA group and diabetes+DCA group (P<0.05). Conclusion: Considering that PGC-1 alpha plays an important role in mitochondrial biogenesis, it is likely that by inhibiting PDK4 and subsequently controlling oxidation of fatty acid (FA) in the heart tissue, oxidative stress in the heart tissue of diabetic patients will be reduced and cardiac efficiency will be increased.