PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease
Yajuan Li, … , Liuqing Yang, Chunru Lin
Yajuan Li, … , Liuqing Yang, Chunru Lin
Published February 11, 2019
Citation Information: J Clin Invest. 2019;129(3):1129-1151. https://doi.org/10.1172/JCI121987.
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Research Article Cell biology Nephrology

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease

Abstract

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 PTENK27-polyUb). Genetic inhibition of PTENK27-polyUb alleviated Col4a3 knockout–, folic acid–, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTENK27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTENK27-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 PTENK27-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 PTENK27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.

Authors

Yajuan Li, Qingsong Hu, Chunlai Li, Ke Liang, Yu Xiang, Heidi Hsiao, Tina K. Nguyen, Peter K. Park, Sergey D. Egranov, Chandrashekar R. Ambati, Nagireddy Putluri, David H. Hawke, Leng Han, Mien-Chie Hung, Farhad R. Danesh, Liuqing Yang, Chunru Lin

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Figure 2

Pten K80R mutant reduces EMT during renal fibrosis.

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Pten K80R mutant reduces EMT during renal fibrosis. (A) Representative i...
(A) Representative images of immunofluorescence staining using indicated antibodies of Col4a3+/– PtenWT/K80R, Col4a3+/– PtenK80R/K80R, Col4a3–/– PtenWT/K80R, and Col4a3–/– PtenK80R/K80R kidneys. Scale bars: 100 μm. (B–C) Statistical analysis of staining intensity of MEX3C (B) and α-SMA (C) per Na+K+-ATPase–positive tubules. Error bars indicate SD; n = 5 animals and 6 independent fields per animal were calculated (1-way ANOVA). (D) Pearson correlation of the staining intensity of Ub-PTEN (K80) with α-SMA per Na+K+-ATPase+ tubule (n = 20, Pearson χ2 test). (E–G) Statistical analysis of TWIST-staining intensity (E), SNAI1-staining intensity (F), and YAP-staining intensity (G) per Na+K+-ATPase positive tubules. Error bars, SD, n = 5 animals and 6 independent fields per animal were calculated (1-way ANOVA). (H) Pearson correlation of the staining intensity of Ub-PTEN (K80) with TWIST, SNAI1, and YAP per Na+K+-ATPase+ tubule (n = 20, Pearson χ2 test). (I–J) Detection of BUN (I), or ACR (J) in blood or urine samples of Col4a3+/– PtenWT/K80R, Col4a3+/– PtenK80R/K80R, Col4a3–/– PtenWT/K80R, and Col4a3–/– PtenK80R/K80R animals. Error bars indicate SD; n = 6, 7, 9, 7 (I); n = 5, 8, 9, 6 (J) respectively (1-way ANOVA). (K) Kaplan-Meier survival analysis of Col4a3+/– PtenWT/K80R, Col4a3+/– PtenK80R/K80R, Col4a3–/– PtenWT/K80R, and Col4a3–/– PtenK80R/K80R animals (n = 5, 5, 17, and 18 respectively, log-rank test). NS indicates P > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.