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FASEB J. 2018 Aug;32(8):4544-4559. doi: 10.1096/fj.201701374R. Epub 2018 Mar 19.

Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

Author information

1
Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
2
Department of Matrix Medicine, Faculty of Medicine, Oita University, Yufu, Japan.
3
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
4
Electron Microscope Core Facility, Niigata University, Niigata, Japan.
5
Yamaguchi's Pathology Laboratory, Matsudo, Japan.
6
University Health Center, Joetsu University of Education, Joetsu, Japan.
7
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
8
Department of Health Promotion Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
9
Future Basic Medicine, Nara Medical University, Kashihara, Japan.
10
GlycoPharma Corporation, Oita, Japan.

Abstract

A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure ( i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules-Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter-that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.-Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

KEYWORDS:

Na+-K+-2Cl− cotransporter; Na+-K+-ATPase; mitochondria-rich cell; polyuria; uromodulin

PMID:
29553830
PMCID:
PMC6071062
DOI:
10.1096/fj.201701374R
[Indexed for MEDLINE]
Free PMC Article

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