title: The Role of Endoplasmic Reticulum Stress in Diabetic Nephropathy.
abstract: Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN. Recent findings suggested that many attributes of DN, such as hyperglycemia, proteinuria, and increased advanced glycation end products and free fatty acids, can all trigger unfolded protein response (UPR) in kidney cells. Herein, we review the current knowledge on the role of ER stress in the setting of kidney injury with a specific emphasis on DN.
  
  
  
  As maladaptive ER stress response caused by excessively prolonged UPR will eventually cause cell death and increase kidney injury, several ER stress inhibitors have been shown to improve DN in animal models, albeit blocking both adaptive and maladaptive UPR. More recently, reticulon-1A (RTN1A), an ER-associated protein, was shown to be increased in both human and mouse diabetic kidneys. Its expression correlates with the progression of DN, and its polymorphisms are associated with kidney disease in people with diabetes. Increased RTN1A expression heightened the ER stress response and renal cell apoptosis, and conversely reduced RTN1A in renal cells decreased apoptosis and ameliorated kidney injury and DN progression, suggesting that RTN1A may be a novel target to specifically restrain the maladaptive UPR. These findings suggest that ER stress response in renal cells is a key driver of progression of DN and that the inhibition of the unchecked ER stress response in DN, such as by inhibition of RTN1A function, may be a promising therapeutic approach against DN.
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1243, New York, NY, 10029, USA.
authors.forename: Kyung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Niansong
authors.initials: N
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1243, New York, NY, 10029, USA. cijiang.he@mssm.edu.|Renal Section, James J Peters VAMC, Bronx, NY, USA. cijiang.he@mssm.edu.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D007684:Kidney Tubules / Q000473:pathology; D050527:Mesangial Cells / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000502:physiology; D056811:Unfolded Protein Response
chemical_list: D009419:Nerve Tissue Proteins; C081781:RTN1 protein, human
keywords: Apoptosis; Diabetic nephropathy; Endoplasmic reticulum stress; Reticulon-1 (RTN-1); Unfolded protein response