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 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.

Endometrial extracellular matrix rigidity and IFNτ ensure the establishment of early pregnancy through activation of YAP

“…We observed that mechanical or chemical stimulation upregulated YAP induced IL‐6 production in bEECs and had no obvious effect on other inflammatory factors (Figure 5E, Figure B), which are proposed to be essential for the formation of the maternal uterine immune environment during the preimplantation period. We also found that IL‐6 positively regulates YAP activation in bEEc cells (Figure 5F), consistent with previous studies in an organ injury model 35,36 . The expression of the uterine receptive markers LIF and VEGF also exhibited a positive correlation with YAP (Figure 5G).…”

“…We also found that IL-6 positively regulates YAP activation in bEEc cells ( Figure 5F), consistent with previous studies in an organ injury model. 35,36 The expression of the uterine receptive markers LIF and VEGF also exhibited a positive correlation with YAP ( Figure 5G). These results indicate that YAP activation provides the conditions required for early pregnancy.…”

RNA packaging into extracellular vesicles: An orchestra of RNA‐binding proteins?

“…identified the small molecule triptolide as an inhibitor of the enzymatic activity of MEX3C, out of 2027 bioactive compounds screened. This natural compound targeted the UBE2S‐MEX3C interaction leading to inhibition of epithelial‐mesenchymal transition in renal epithelial cells (Li et al., 2019).…”

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

“…Folic acid-induced renal hypertrophy was first observed in rats in the 1960s, though it has never been reported in humans [76,77,78]. Ever since, the mechanisms underlying folic acid-induced kidney injury have been investigated, partially characterized, and, to this day, considered a valuable animal model to study acute kidney injury onset, progression, and possible protective strategies [78,79,80,81,82].…”