PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease
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
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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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 4

PTENK27-polyUb is correlated with DKD.

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PTENK27-polyUb is correlated with DKD. (A) Presence of PTENK27-polyUb in...
(A) Presence of PTENK27-polyUb in human serum samples from healthy donors, type 1 diabetic patients, type 2 diabetic patients, or patients with DKD (n = 16, 12, 13, 13 serum samples, respectively; 1-way ANOVA). (B) Pearson’s correlation of serum PTENK27-polyUb with eGFR (n = 54 serum, Pearson χ2 test). (C) Pearson’s correlation of serum PTENK27-polyUb with eGFR of DKD patients (n = 13 serum, Pearson χ2 test). (D) ROC curves for analytes in serum PTENK27-polyUb for the diagnosis of DKD patients. (E) Pearson’s correlation of serum PTENK27-polyUb with blood glucose level in patients with type 1/2 diabetes and DKD (n = 38 serum, Pearson χ2 test). (F–G) Representative images (F) and statistical analysis of immunofluorescence staining of MEX3C (G, left) and PTENK27-polyUb (G, right) and in kidney tissues of healthy donors and DKD patients. Error bar indicates SD of staining intensities of 6 random fields per tissue (n = 9 and 9, respectively; Student’s t test). Scale bars: 100 μm. (H) Pearson’s correlation of MEX3C and PTENK27-polyUb in human kidney tissues (n = 18, Pearson χ2 test). (I) Measurement of PTENK27-polyUb concentration in human urine samples from healthy donors or DKD patients (n=10 and 6 urine samples), Error bars, SD, Student’s t-test. (J) Pearson’s correlation of urine PTENK27-polyUb with eGFR of healthy and DKD patients (n=16 urine samples, Pearson χ2 test). (K) Measurement of PTENK27-polyUb concentration in paired serum and urine samples of healthy donors, type 2 diabetes patients, and DKD patients (n = 11, Pearson χ2 test). NS indicates P > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.