C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation

Abstract

Hypertrophy is a prominent feature of damaged podocytes in diabetic kidney disease (DKD). mTORC1 hyperactivation leads to podocyte hypertrophy, but the detailed mechanism of how mTORC1 activation occurs under pathological conditions is not completely known. Moreover, reduced nephrin tyrosine phosphorylation has been observed in podocytes under pathological conditions, but the molecular mechanism linking nephrin phosphorylation and pathology is unclear so far. In this study, we observed a significant increase in C1-Ten level in diabetic kidney and in high glucose-induced damaged podocytes. C1-Ten acts as a protein tyrosine phosphatase (PTPase) at the nephrin-PI3K binding site and renders PI3K for IRS-1, thereby activating mTORC1. Furthermore, C1-Ten causes podocyte hypertrophy and proteinuria by increasing mTORC1 activity in vitro and in vivo. These findings demonstrate the relationship between nephrin dephosphorylation and the mTORC1 pathway, mediated by C1-Ten PTPase activity. We suggest that C1-Ten contributes to the pathogenesis of DKD by inducing podocyte hypertrophy under high glucose conditions.

Deletion of the Tensin2 SH2-PTB domain, but not the loss of its PTPase activity, induces podocyte injury in FVB/N mouse strain

“…This mTOrC1 activation is associated with podocyte dysfunction in diabetic nephropathy [5,10] and, interestingly, TNS2 is upregulated in diabetic nephropathy model glomeruli [11]. adenovirus-mediated Tns2 overexpression induces mTOrC1 activation and podocyte dysfunction in a PTPase-dependent manner [11]. On the other hand, decreased mTOrC1 activity also induces podocyte dysfunction after birth [5].…”

“…Additionally, the effect of mTORC1 activity on podocytes seems to be modified by the age and genetic background of the mice [5]. Thus, we expected that decreased mTOrC1 activity by the embryonic inactivation of the TNS2 PTPase domain might induce podocyte injury in mice with a diabetic nephropathy-susceptible FVB genetic background [30], while transient Tns2 CS overexpression did not induce podocyte injury in adult DBa/2 mice [11]. However, Tns2 CS mice developed neither podocyte dysfunction nor proteinuria.…”

“…signaling in podocytes through its action as a PTPase toward nephrin, which is a principal podocyte slit diaphragm component [11]. This mTOrC1 activation is associated with podocyte dysfunction in diabetic nephropathy [5,10] and, interestingly, TNS2 is upregulated in diabetic nephropathy model glomeruli [11]. adenovirus-mediated Tns2 overexpression induces mTOrC1 activation and podocyte dysfunction in a PTPase-dependent manner [11].…”

“…Tns2 CS mice with an FVB genetic background (hereafter simply, Tns2 CS mice) were generated by CriSPr/Cas9mediated genome editing as described previously [17]. Briefly, the guide RNA (gRNA) guiding sequence for the catalytic site of the PTPase domain (NCBi accession numbers NM_001355636 and NM_153533) was designed as follows: 5'-CgTggTTgTgTTgTaCTg-Ca-3' (where the underlined residues correspond to an essential catalytic residue Cys231 [6,11]). From the DNa oligonucleotides consisting of tandemly arranged T7 promoter and grNa sequences, grNa was transcribed in vitro using the MEgashortscript T7 kit (Thermo Fisher Scientific, waltham, Ma, uSa).…”

“…in this study, we generated a novel mutant mouse carrying a missense mutation (p.Cys231Ser) in TNS2 (designated Tns2 CS , Fig. 1), resulting in the catalytic inactivation of the PTPase domain [6,11]. we then assessed the effects of these Tns2 mutations (Tns2 nph , Tns2 ∆C and Tns2 CS ) on podocytes in mice with an FVB genetic background to investigate the contribution of each of the SH2-PTB and PTPase domains to podocyte maintenance.…”