title: CD2-associated protein/phosphoinositide 3-kinase signaling has a preventive role in angiotensin II-induced podocyte apoptosis.
abstract: Angiotensin II (Ang II) works as a paracrine or autocrine cytokine agent to regulate renal functions and promotes podocytes dysfunction directly or indirectly, causing proteinuria. The glomerular slit diaphragm (SD) serves as a size-selective barrier and is linked to the actin-based cytoskeleton by adaptor proteins, including CD2-associated protein (CD2AP). Therefore, damages to CD2AP affect not only the function of the SD, but also directly disrupt the podocyte cytoskeleton, leading to proteinuria. In addition, CD2AP can facilitate the nephrin-induced phosphoinositide 3-kinase (PI3-K)/Akt signaling, which protects podocytes from apoptosis. Here we found that CD2AP staining was located diffusely but predominantly in the peripheral cytoplasm and CD2AP co-localized with nephrin in mouse podocytes; however, Ang II decreased CD2AP staining diffusely and induced a separation from concentrated nephrin. Ang II notably reduced CD2AP expression in time- and concentration-dependent manners, and this was significantly recovered by losartan. Ang II induced podocyte apoptosis in time- and concentration-dependent manners in TUNEL and FACS assays. LY294002, a PI3-K inhibitor, further reduced CD2AP expression and increased podocyte apoptosis, which was augmented by siRNA for CD2AP. Thus, Ang II induces the relocalization and reduction of CD2AP via AT1R, which would cause podocyte apoptosis by the suppression of CD2AP/PI3-K signaling.
authors: Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
authors: Hye-Young
authors: HY
authors: Park
authors: Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
authors: Su-Bin
authors: SB
authors: Seong
authors: Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
authors: Seo-Yun
authors: SY
authors: Min
authors: Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea. Electronic address: tsha@chungbuk.ac.kr.
authors: Tae-Sun
authors: TS
authors: Ha
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D002867:Chromones; D003598:Cytoskeletal Proteins; D009025:Morpholines; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases
keywords: Angiotensin II; Apoptosis; CD2-associated protein; Phosphoinositide 3-kinase; Podocyte