TY - JOUR
T1 - A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease
AU - Nakatsuka, Atsuko
AU - Yamaguchi, Satoshi
AU - Eguchi, Jun
AU - Kakuta, Shigeru
AU - Iwakura, Yoichiro
AU - Sugiyama, Hitoshi
AU - Wada, Jun
N1 - Funding Information:
We thank M. Matsuyama and M. Fukushima for technical and clinical suggestions. We acknowledge support from Central Research Laboratory, Okayama University Medical School; usage of BECKMAN COULTER XL 80, ABI PRISM3130, and producing paraffin blocks and sections. This work was supported by a Grant-in-Aid for Scientific Research (C) 26461361, Japan Diabetes Foundation, Grants for young researchers from Japan Association for Diabetes Education and Care, Mochida Memorial Foundation for Medical and Pharmaceutical Research, The Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, The Okayama Medical Foundation, Japan medical Women’s Association, Suzuken Memorial Foundation, Yukiko Ishibashi Foundation, and SHISEIKAI Scientific Award to A.N.
Funding Information:
J.W. receives speaker honoraria from Astra Zeneca, Daiichi Sankyo, MSD, Novartis, Tanabe Mitsubishi, Taisho Toyama and receives grant support from Baxter, Chugai, Dainippon Sumitomo, Ono, Teijin. All other authors declare no competing interests.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin−/− obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.
AB - Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin−/− obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.
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U2 - 10.1038/s42003-021-01902-y
DO - 10.1038/s42003-021-01902-y
M3 - Article
C2 - 33742129
AN - SCOPUS:85102699365
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 373
ER -
