title: Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway, resulting in reduced podocyte injury.
abstract: The podocyte functions as a glomerular filtration barrier. Autophagy of postmitotic cells is an important protective mechanism that is essential for maintaining the homeostasis of podocytes. Exploring an in vivo rat model of passive Heymann nephritis and an in vitro model of puromycin amino nucleotide (PAN)-cultured podocytes, we examined the specific mechanisms underlying changing autophagy levels and podocyte injury. In the passive Heymann nephritis model rats, the mammalian target-of-rapamycin (mTOR) levels were upregulated in injured podocytes while autophagy was inhibited. In PAN-treated podocytes, mTOR lowered the level of autophagy through the mTOR-ULK1 pathway resulting in damaged podocytes. Rapamycin treatment of these cells reduced podocyte injury by raising the levels of autophagy. These in vivo and in vitro experiments demonstrate that podocyte injury is associated with changes in autophagy levels, and that rapamycin can reduce podocyte injury by increasing autophagy levels via inhibition of the mTOR-ULK1 pathway. These results provide an important theoretical basis for future treatment of diseases involving podocyte injury.
authors.affiliation: State Key Laboratory of Kidney Diseases, Department of Nephrology, PLA General Hospital and Military Medical Postgraduate College, Beijing, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Wu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Cui
authors.forename: Kai
authors.initials: K
authors.lastname: Hou
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhou
authors.forename: Guangyan
authors.initials: G
authors.lastname: Cai
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Xie
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D015433:Glomerulonephritis, Membranous / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D050199:Podocytes / Q000166:cytology* / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics
chemical_list: C561242:Atg7 protein, rat; D034741:RNA, Small Interfering; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D020123:Sirolimus