Angiopoietin2-mediated caveolin1 phosphorylation regulating transcytosis of renal tubular epithelial cell contributes to the occurrence of albuminuria under high glucose exposure.

Background: Microlbuminuria is the earliest clinical evidence of diabetic kidney disease (DKD) and contributes to the induction and/or progression of DKD. Previous studies have shown that increased expression of angiopoietin2 (ANGPT2) is correlated with an increase in albuminuria. However, the critical role of ANGPT2 in albuminuria development remains unclear. Some studies have shown the significance of transcytosis in the occurrence of albuminuria, but it is unknown whether it takes place in albumin recycling in renal tubular cells of patients with DKD. Furthermore, the potential mechanism of this association also remains unclear.

Methods: In this study, human renal tubular epithelial cells (HK-2) were cultured with high glucose in a Transwell plate to establish a transcytosis model, while C57BL/6 mice were intraperitoneally injected with streptozotocin to establish a DKD model. The expression of ANGPT2 and caveolin1 (CAV1) phosphorylation was dectected through immunohistochemistry and western blot analysis.

Results: Transcytosis of albumin in renal tubular epithelial cells was downregulated after high glucose exposure, and increased expression of ANGPT2 and CAV1 phosphorylation both in vivo and in vitro was observed. Inhibition of ANGPT2 and CAV1 independently promoted transcytosis. Furthermore, ANGPT2 downregulation inhibited CAV1 phosphorylation, whereas CAV1 phosphorylation had no effect on the expression of ANGPT2.

Conclusions: ANGPT2 reduces albumin transcytosis across renal tubular epithelial cells under high glucose conditions by activating CAV1 phosphorylation, thus increasing albuminuria in DKD. These findings suggested that ANGPT2 and CAV1 may be promising therapeutic targets for albuminuria in DKD.