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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adipokines / genetics
-
Adipokines / metabolism*
-
Animals
-
Apoptosis
-
Autophagy
-
Cell Line
-
Clathrin / metabolism
-
Diabetic Nephropathies / etiology
-
Diabetic Nephropathies / genetics
-
Diabetic Nephropathies / metabolism*
-
Diabetic Nephropathies / pathology
-
Diet, High-Fat
-
Disease Models, Animal
-
Endocytosis
-
Endoplasmic Reticulum Chaperone BiP
-
Endoplasmic Reticulum Stress*
-
HSP70 Heat-Shock Proteins / genetics
-
HSP70 Heat-Shock Proteins / metabolism*
-
Heat-Shock Proteins / metabolism
-
Humans
-
Inflammasomes / metabolism
-
Kidney Tubules, Proximal / metabolism*
-
Kidney Tubules, Proximal / pathology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Obesity / complications
-
Organelles / metabolism*
-
Organelles / pathology
-
Protein Binding
-
Serpins / genetics
-
Serpins / metabolism*
-
Signal Transduction
Substances
-
Adipokines
-
Clathrin
-
Endoplasmic Reticulum Chaperone BiP
-
HSP70 Heat-Shock Proteins
-
HSPA1L protein, human
-
HSPA5 protein, human
-
Heat-Shock Proteins
-
Hspa1l protein, mouse
-
Hspa5 protein, mouse
-
Inflammasomes
-
SERPINA12 protein, human
-
Serpins
-
vaspin protein, mouse