A Vaspin\u2013HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease

Atsuko Nakatsuka,Jun Wada,Satoshi Yamaguchi,Jun Eguchi,Yoichiro Iwakura,Shigeru Kakuta,Hitoshi Sugiyama

doi:10.1038/s42003-021-01902-y

Abstract

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.

Highlights

Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD)
We revealed the beneficial mechanisms of vaspin on PTCs through vaspin interactive molecules, i.e., GRP78 and heat shock protein family A (Hsp70) member 1 like (HSPA1L); both molecules belong to heat shock protein 70s family
These findings indicated that lysosomal enlargement in proximal tubular cells was enhanced in diet-induced obese vaspin−/− mice, while vacuolar formation was ameliorated in vaspin Tg mice

Summary

Introduction

Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). 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. 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. Obesity is recognized as a major risk factor for a sustained decline of renal function in DKD patients. GRP78 is known as an ER stress-associated protein, recently it is reported to translocate from ER to plasma membrane by several cellular stresses[13]

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