TY - JOUR
T1 - PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease
AU - Li, Yajuan
AU - Hu, Qingsong
AU - Li, Chunlai
AU - Liang, Ke
AU - Xiang, Yu
AU - Hsiao, Heidi
AU - Nguyen, Tina K.
AU - Park, Peter K.
AU - Egranov, Sergey D.
AU - Ambati, Chandrashekar R.
AU - Putluri, Nagireddy
AU - Hawke, David H.
AU - Han, Leng
AU - Hung, Mien Chie
AU - Danesh, Farhad R.
AU - Yang, Liuqing
AU - Lin, Chunru
N1 - Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/3
Y1 - 2019/3
N2 - Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTEN K27-polyUb ). Genetic inhibition of PTEN K27-polyUb alleviated Col4a3 knockout–, folic acid–, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTEN K27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTEN K27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTEN K27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout–, folic acid–injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTEN K27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.
AB - Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTEN K27-polyUb ). Genetic inhibition of PTEN K27-polyUb alleviated Col4a3 knockout–, folic acid–, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTEN K27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTEN K27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTEN K27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout–, folic acid–injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTEN K27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.
UR - http://www.scopus.com/inward/record.url?scp=85062089609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062089609&partnerID=8YFLogxK
U2 - 10.1172/JCI121987
DO - 10.1172/JCI121987
M3 - Article
C2 - 30741721
AN - SCOPUS:85062089609
SN - 0021-9738
VL - 129
SP - 1129
EP - 1151
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 3
ER -