Ubiquitylation of PTEN drives fibrosis in diabetic kidney disease

Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus, with progressive renal fibrosis often leading to end-stage renal disease. Factors such as hyperglycaemia, growth factors and the transcription factors TWIST and SNAI1 are known to contribute to fibrosis, but approaches to therapeutically target these factors are limited. New findings show that a modified form of phosphatase and tensin homologue (PTEN) — characterized by linkage of a polyubiquitin chain at lysine 27 (referred to as PTEN^K27-polyUb) — promotes partial epithelial-to-mesenchymal transition (EMT) and renal fibrosis in DKD and can be targeted to improve renal outcomes in models of DKD. “Our studies demonstrate that PTEN^K27-polyUb can be used for the early diagnosis of DKD and that targeting PTEN^K27-polyUb with the small molecule triptolide is a new therapeutic option for kidney fibrosis,” say Liuqing Yang and Chunru Lin.

Credit: Lara Crow/Springer Nature Limited

Yang and Lin say that their previous work, showing that PTEN^K27-polyUb correlates with EMT in renal tubular epithelial cells, led them to propose that PTEN^K27-polyUb could be used to stratify patients at risk of DKD. PTEN^K27-polyUb promotes dephosphorylation and stabilization of TWIST and SNAI1, resulting in enhanced EMT. In mice, genetic inhibition of PTEN^K27-polyUb attenuated histological and functional indices of kidney injury induced by Col4a3 deletion, or by administration of folic acid or streptozotocin. In patients with diabetes mellitus, serum and urine levels of PTEN^K27-polyUb were higher than those of healthy controls and correlated negatively with estimated glomerular filtration rate.

The researchers then used a high-throughput assay to screen small molecular inhibitors that target MEX3C — the E3 ligase that catalyses PTEN^K27-polyUb. “More than 2,000 bioactive compounds were tested using this method and triptolide was identified as one of the top candidates that effectively inhibited MEX3C enzymatic activity,” say Yang and Lin. Treatment with triptolide inhibited PTEN^K27-polyUb-mediated EMT of renal epithelial cells, reduced levels of TWIST and SNAI1 and improved outcomes in models of DKD.

targeting PTEN^K27-polyUb ... is a new therapeutic option for kidney fibrosis

The researchers say their study findings suggest that identification of PTEN^K27-polyUb might facilitate early diagnosis of DKD and represent a viable therapeutic target. “We plan to validate PTEN^K27-polyUb as a biomarker in a larger cohort of patients in order to further demonstrate its value in stratifying at-risk patient populations,” they say.