title: SIRPα signaling regulates podocyte structure and function.
abstract: Signal-regulatory protein-α (SIRPα) is a transmembrane protein that contains tyrosine phosphorylation sites in its cytoplasmic region; two tyrosine phosphatases, SHP-1 and SHP-2, bind to these sites in a phosphorylation-dependent manner and transduce multiple intracellular signals. Recently, SIRPα was identified as one of the major tyrosine-phosphorylated proteins in the glomeruli and found to be expressed in podocytes. In the present study, we examined the role of SIRPα expression in podocytes using knockin mice (C57BL/6 background) expressing mutant SIRPα that lacks a cytoplasmic region (SIRPα-mutant mice). Light microscopic examination revealed no apparent morphological abnormalities in the kidneys of the SIRPα-mutant mice. On the other hand, electron microscopic examination revealed abnormal podocytes with irregular major processes and wider and flattened foot processes in the SIRPα-mutant mice compared with their wild-type counterparts. Significantly impaired renal functions and slight albuminuria were demonstrated in the SIRPα-mutant mice. In addition, adriamycin injection induced massive albuminuria together with focal glomerulosclerosis in the SIRPα-mutant mice, while their wild-type counterparts were resistant to adriamycin-induced nephropathy. These data demonstrate that SIRPα is involved in the regulation of podocyte structure and function as a filtration barrier under both physiological and pathological conditions.
authors.affiliation: Dept. of Medicine and Clinical Science, Gunma Univ. Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. hiromura@gunma-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Mai
authors.initials: M
authors.lastname: Tomioka
authors.forename: Keiju
authors.initials: K
authors.lastname: Hiromura
authors.forename: Toru
authors.initials: T
authors.lastname: Sakairi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hamatani
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ikeuchi
authors.forename: Yoriaki
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Akito
authors.initials: A
authors.lastname: Maeshima
authors.forename: Takeo
authors.initials: T
authors.lastname: Aoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nojima
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D004317:Doxorubicin / Q000633:toxicity; D005921:Glomerulonephritis / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D050199:Podocytes / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D018909:src Homology Domains
chemical_list: C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D004317:Doxorubicin
keywords: SIRPα; adriamycin nephropathy; podocytes; proteinuria