Pit 1 transporter (SLC20A1) as a key factor in the NPP1‐mediated inhibition of insulin signaling in human podocytes

Abstract

Podocytes are crucially involved in blood filtration in the glomerulus. Their proper function relies on efficient insulin responsiveness. The insulin resistance of podocytes, defined as a reduction of cell sensitivity to this hormone, is the earliest pathomechanism of microalbuminuria that is observed in metabolic syndrome and diabetic nephropathy. In many tissues, this alteration is mediated by the phosphate homeostasis‐controlling enzyme nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). By binding to the insulin receptor (IR), NPP1 inhibits downstream cellular signaling. Our previous research found that hyperglycemic conditions affect another protein that is involved in phosphate balance, type III sodium‐dependent phosphate transporter 1 (Pit 1). In the present study, we evaluated the insulin resistance of podocytes after 24 h of incubation under hyperinsulinemic conditions. Thereafter, insulin signaling was inhibited. The formation of NPP1/IR complexes was observed at that time. A novel finding in the present study was our observation of an interaction between NPP1 and Pit 1 after the 24 h stimulation of podocytes with insulin. After downregulation of the SLC20A1 gene, which encodes Pit 1, we established insulin resistance in podocytes that were cultured under native conditions, manifested as a lack of intracellular insulin signaling and the inhibition of glucose uptake via the glucose transporter type 4. These findings suggest that Pit 1 might be a major factor that participates in the NPP1‐mediated inhibition of insulin signaling.

Free Amino Acids Accelerate the Time-Dependent Inactivation of Rat Liver Nucleotide Pyrophosphatase / Phosphodiesterase Enpp3 elicited by EDTA

“…(iv) Finally, an important function attributed to ENPP1 is the inhibition of the insulin receptor tyrosine kinase by ENPP1, which has a role in the insulin resistance of non-insulin-dependent diabetes mellitus (Arianti et al 2021; Goldfine et al 1998; Goldfine et al 2008; Goldfine et al 1999; Maddux et al 1995; Roberts et al 2019; Teno et al 1999). In this case there is contradictory evidence, still unresolved, for the dependence of the inhibition of the insulin receptor on the enzyme activity of ENPP1 (Chin et al 2009; Grupe et al 1995; Stefan et al 1996), but anyhow such inhibition has been repeatedly related to a direct contact between both membrane proteins (Di Paola et al ; Dimatteo et al 2013; Kulesza et al 2023; Maddux et al 1995; Tassone et al 2018).…”