title: Nicousamide protects kidney podocyte by inhibiting the TGFβ receptor II phosphorylation and AGE-RAGE signaling.
abstract: Nicousamide, a clinical phase II renal protective new drug, has been demonstrated to have renal protective effect on diabetic nephropathy (DN) by experimental animal model. Its known molecular mechanisms include AGE formation blocking and moderately decreasing the blood pressure. Nicousamide shows potential on attenuating albuminuria, thereby suggests it might have protective effect on podocytes. The aim of present study was to investigate whether nicousamide could protect integrity of podocytes, and further its protection mechanisms. Sprague-Dawley (SD) rats were induced to DN by streptozotocin, and nicousamide (20 and 40 mg/kg) was orally administrated for 20 weeks. Every five weeks, the albuminuria was measured, and renal pathology was evaluated at the end of experiment. Real-time PCR and immunofluorescence were used to test expression of podocyte marker nephrin, CD2AP and podocine in rat kidney tissues. Western blot was used to test the activation and phosphorylation of TGFβ1-smad signaling pathway. surface plasmon resonance (SPR) technology was used to analyze whether nicousamide can interact with TGFβ1 receptor II (TGFβ RII) and receptor for advanced glycation endproducts (RAGE). Results demonstrate that nicousamide significantly reduces albuminuria and ameliorate the glomerulosclerosis in DN rats. RT-PCR and immunofluorescence demonstrate that nicousamide can increase the expression of podocyte markers and keep podocyte effacement. Phosphorylation of TGFβ RII and smad2 in rat kidney was inhibited by nicousamide dose dependently. SPR demonstrate that nicousamide have strong binding capability with hRAGE with Kd approximate 6 μM. These results indicate a protective effect of nicousamide against podocyte injury, and this effect might contribute from suppression of TGFβ-involved fibrosis and AGE-RAGE signaling activation.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Sen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Dongjie
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Nina
authors.initials: N
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, P. R. China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
keywords: Nicousamide; RAGE; TGFβ receptor II; diabetic nephropathy; nephrin; podocyte