SDF2L1 downregulation mediates high glucose-caused Schwann cell dysfunction by inhibiting nuclear import of TFEB and CREB via KPNA3

Abstract

Schwann cells dysfunction is a key contributor to diabetic peripheral neuropathy (DPN), affecting both neurons and blood vessels. However, the precise mechanisms underlying high glucose-induced Schwann cells dysfunction are still not fully elucidated. In the present study, we investigated the expression, function and molecular mechanisms of SDF2L1 in Schwann cells using diabetic mice, SDF2L1 KO mice, rat Schwann cell (RSC96) and primary rat Schwann cell (PRSC). The RNA-seq of high glucose-treated RSC96 cells revealed an evident downregulation of SDF2L1 at both 48 and 72 h. The inhibition of high glucose on SDF2L1 expression was further confirmed at the levels of mRNA and protein in RSC96 and PRSC cells. Again, reduced SDF2L1 expression was also observed in the sciatic nerves of both type 1 and 2 diabetic mice. Functional exploration revealed that SDF2L1 knockdown in RSC96 cells suppressed the expression of LC3-II, P62, BDNF, NGF and IGF. In vivo SDF2L1 KO also decreased these proteins expression in the sciatic nerve of C57BL/6 J mice, along with the reduced nerve conduction velocity and action potential amplitude. Then, proteomics analyses and biological experiments demonstrated that SDF2L1 knockdown significantly decreased KPNA3 expression in RSC96 cells. Overexpression of KPNA3 ameliorated the decreases in LC3-II, P62, BDNF, NGF and IGF caused by SDF2L1 downregulation in vitro. Moreover, KPNA3 affected the nuclear import of transcription factors TFEB and CREB in RSC96 cells. Next, KPNA3 overexpression reversed SDF2L1 KO-reduced the nuclear aggregation of TFEB and CREB, and the expression of LC3, P62, BDNF and NGF in vivo. Collectively, these findings suggest that decreased SDF2L1 inhibits cell autophagy and neurotrophin expression by impeding the nuclear import of TFEB and CREB via KPNA3 downregulation in high glucose-treated Schwann cells.