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

Abstract

Tensin2 (TNS2) is a focal adhesion-localized protein possessing N-terminal tandem protein tyrosine phosphatase (PTPase) and C2 domains, and C-terminal tandem Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains. Genetic deletion of Tns2 in a susceptible murine strain leads to podocyte alterations after birth. To clarify the domain contributions to podocyte maintenance, we generated two Tns2-mutant mice with the genetic background of the susceptible FVB/NJ strain, Tns2^∆C and Tns2^CS mice, carrying a SH2-PTB domain deletion and a PTPase domain inactivation, respectively. The Tns2^∆C mice developed massive albuminuria, severe glomerular injury and podocyte alterations similarly to those in Tns2-deficient mice. In contrast, the Tns2^CS mice showed no obvious phenotypic abnormalities. These results indicate that the TNS2 SH2-PTB domain, but not its PTPase activity, plays a role in podocyte maintenance. Furthermore, in a podocyte cell line, the truncated TNS2 mutant lacking the SH2-PTB domain lost the ability to localize to focal adhesion. Taken together, these data suggest that TNS2 recruitment to focal adhesion is required to maintain postnatal podocytes on a susceptible genetic background.

Keywords: chronic kidney disease; focal adhesion; nephropathy; podocyte; tensin.