title: Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease.
abstract: Obesity, an important risk factor for metabolic syndrome (MetS) and cardiovascular disease, is often complicated by CKD, which further increases cardiovascular risk and causes ESRD. To elucidate the mechanism underlying this relationship, we investigated the role of the endocytic receptor megalin in proximal tubule epithelial cells (PTECs). We studied a high-fat diet (HFD)-induced obesity/MetS model using kidney-specific mosaic megalin knockout (KO) mice. Compared with control littermates fed a normal-fat diet, control littermates fed an HFD for 12 weeks showed autolysosomal dysfunction with autophagy impairment and increased expression of hypertrophy, lipid peroxidation, and senescence markers in PTECs of the S2 segment, peritubular capillary rarefaction with localized interstitial fibrosis, and glomerular hypertrophy with mesangial expansion. These were ameliorated in HFD-fed megalin KO mice, even though these mice had the same levels of obesity, dyslipidemia, and hyperglycemia as HFD-fed control mice. Intravital renal imaging of HFD-fed wild-type mice also demonstrated the accumulation of autofluorescent lipofuscin-like substances in PTECs of the S2 segment, accompanied by focal narrowing of tubular lumens and peritubular capillaries. In cultured PTECs, fatty acid-rich albumin induced the increased expression of genes encoding PDGF-B and monocyte chemoattractant protein-1 via megalin, with large (auto)lysosome formation, compared with fatty acid-depleted albumin. Collectively, the megalin-mediated endocytic handling of glomerular-filtered (lipo)toxic substances appears to be involved primarily in hypertrophic and senescent PTEC injury with autophagy impairment, causing peritubular capillary damage and retrograde glomerular alterations in HFD-induced kidney disease. Megalin could be a therapeutic target for obesity/MetS-related CKD, independently of weight, dyslipidemia, and hyperglycemia modification.
authors.affiliation: Department of Applied Molecular Medicine.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kuwahara
authors.affiliation: Department of Clinical Nutrition Science.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hosojima
authors.affiliation: Department of Applied Molecular Medicine.
authors.forename: Reika
authors.initials: R
authors.lastname: Kaneko
authors.affiliation: Department of Applied Molecular Medicine.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan; and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.affiliation: Division of Clinical Nephrology and Rheumatology, and.
authors.forename: Taiji
authors.initials: T
authors.lastname: Sasagawa
authors.affiliation: Division of Clinical Nephrology and Rheumatology, and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kabasawa
authors.affiliation: Department of Clinical Nutrition Science.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kaseda
authors.affiliation: Division of Clinical Nephrology and Rheumatology, and.
authors.forename: Ryota
authors.initials: R
authors.lastname: Yasukawa
authors.affiliation: Division of Clinical Nephrology and Rheumatology, and.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Division of Clinical Nephrology and Rheumatology, and.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Applied Molecular Medicine.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;
authors.forename: Shun
authors.initials: S
authors.lastname: Kageyama
authors.affiliation: Protocol Data Center, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Protocol Data Center, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kitamura
authors.affiliation: Division of Clinical Nephrology and Rheumatology, and.
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Applied Molecular Medicine, akisaito@med.niigata-u.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D004847:Epithelial Cells; D007674:Kidney Diseases / Q000209:etiology*; D007678:Kidney Glomerulus / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse
keywords: Pathophysiology of Renal Disease and Progression; endocytosis; fibrosis; lipids; obesity; proximal tubule