Rtn1a-Mediated Endoplasmic Reticulum Stress in Podocyte Injury and Diabetic Nephropathy.
We previously reported a critical role of reticulon (RTN) 1A in mediating endoplasmic reticulum (ER) stress in kidney tubular cells and the expression of RTN1A correlates with the renal function and the severity of kidney injury in patients with diabetic nephropathy (DN). Here, we determined the roles of RTN1A and ER stress in podocyte injury and DN. We used db/db mice with early unilateral nephrectomy (Unx) as a murine model of progressive DN and treated mice with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress. We found increased expression of RTN1A and ER stress markers in the kidney of db/db-Unx mice. Treatment of TUDCA not only attenuated proteinuria and kidney histological changes, but also ameliorated podocyte and glomeruli injury in diabetic mice, which were associated with reduction of RTN1A and ER stress marker expression in the podocytes of TUDCA-treated mice. In vitro, we showed RTN1A mediates albumin-induced ER stress and apoptosis in human podocytes. A positive feedback loop between RTN1A and CHOP was found leading to an enhanced ER stress in podocytes. Our data suggest that ER stress plays a major role in podocyte injury in DN and RTN1A might be a key regulator of ER stress in podocytes.
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Ying
Y
Fan
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Jing
J
Zhang
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, United States.
Wenzhen
W
Xiao
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, United States.
Kyung
K
Lee
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, United States.
Zhengzhe
Z
Li
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Jiejun
J
Wen
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Li
L
He
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Dingkun
D
Gui
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Rui
R
Xue
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Guihua
G
Jian
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Xiaohua
X
Sheng
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, United States. cijiang.he@mssm.edu.|Renal Section, James J Peter Veterans Administration Medical Center, Bronx, NY, United States. cijiang.he@mssm.edu.
John Cijiang
JC
He
Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. wangniansong2012@163.com.
Niansong
N
Wang
D000818:Animals; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050199:Podocytes / Q000473:pathology* / Q000502:physiology*
D009419:Nerve Tissue Proteins; C489914:Rtn1 protein, mouse