title: Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD.
abstract: Studies have revealed many analogies between podocytes and neurons, and these analogies may be key to elucidating the pathogenesis of podocyte injury. Cathepsin D (CD) is a representative aspartic proteinase in lysosomes. Central nervous system neurons in CD-deficient mice exhibit a form of lysosomal storage disease with a phenotype resembling neuronal ceroid lipofuscinoses. In the kidney, the role of CD in podocytes has not been fully explored. Herein, we generated podocyte-specific CD-knockout mice that developed proteinuria at 5 months of age and ESRD by 20-22 months of age. Immunohistochemical analysis of these mice showed apoptotic podocyte death followed by proteinuria and glomerulosclerosis with aging. Using electron microscopy, we identified, in podocytes, granular osmiophilic deposits (GRODs), autophagosome/autolysosome-like bodies, and fingerprint profiles, typical hallmarks of CD-deficient neurons. CD deficiency in podocytes also led to the cessation of autolysosomal degradation and accumulation of proteins indicative of autophagy impairment and the mitochondrial ATP synthase subunit c accumulation in the GRODs, again similar to changes reported in CD-deficient neurons. Furthermore, both podocin and nephrin, two essential components of the slit diaphragm, translocated to Rab7- and lysosome-associated membrane glycoprotein 1-positive amphisomes/autolysosomes that accumulated in podocyte cell bodies in podocyte-specific CD-knockout mice. We hypothesize that defective lysosomal activity resulting in foot process effacement caused this accumulation of podocin and nephrin. Overall, our results suggest that loss of CD in podocytes causes autophagy impairment, triggering the accumulation of toxic subunit c-positive lipofuscins as well as slit diaphragm proteins followed by apoptotic cell death.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan;
authors.forename: Kanae
authors.initials: K
authors.lastname: Yamamoto-Nonaka
authors.affiliation: Department of Cell Biology and Neuroscience.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; TMK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan;
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takagi
authors.affiliation: TMK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Juan Alejandro
authors.initials: JA
authors.lastname: Oliva Trejo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan;
authors.forename: Takuto
authors.initials: T
authors.lastname: Seki
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan;
authors.forename: Teruo
authors.initials: T
authors.lastname: Hidaka
authors.affiliation: Department of Anatomy and Life Structure, and.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ichimura
authors.affiliation: Department of Anatomy and Life Structure, and.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Division of Genome Research, Research Institute for Diseases of Old Ages.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Tada
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan; and.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; yasu@juntendo.ac.jp.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000473:pathology; D011507:Proteinuria / Q000209:etiology*; D051436:Renal Insufficiency, Chronic / Q000209:etiology*
chemical_list: D002402:Cathepsin D; C533923:Ctsd protein, mouse
keywords: Autophagy; Cathepsin D; Lysosome; glomerulosclerosis; podocyte; subunit c of mitochondrial ATP synthase
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