Modulation of diabetic kidney disease markers by an antagonist of p75NTR in streptozotocin-treated mice

Abstract

Two therapeutic agents targeting p75NTR pathways have been recently developed to alleviate retinopathy and bladder dysfunction in diabetes mellitus (DM), namely the small molecule p75NTR antagonist THX-B and a monoclonal antibody (mAb) that neutralizes the receptor ligand proNGF. We herein explore these two components in the context of diabetic kidney disease (DKD).Streptozotocin-injected mice were treated for 4 weeks with THX-B or anti-proNGF mAb. Kidneys were taken for quantification of microRNAs and mRNAs by RT-qPCR and for detection of proteins by immunohistochemistry, immunoblotting and ELISA. Blood was sampled to measure plasma levels of urea, creatinine, and albumin. DM led to increases in plasma concentrations of urea and creatinine and decreases in plasma albumin. Receptor p75NTR was expressed in kidneys and its expression was decreased by DM. All these changes were reversed by THX-B treatment while the effect of mAb was less pronounced. MicroRNAs tightly linked to DKD (miR-21-5p, miR-214-3p and miR-342-3p) were highly expressed in diabetic kidneys compared to healthy ones. Also, miR-146a, a marker of kidney inflammation, and mRNA levels of Fn-1 and Nphs, two markers of fibrosis and inflammation, were elevated in DM. Treatments with THX-B or mAb partially or completely reduced the expression of the aforementioned microRNAs and mRNAs. P75NTR antagonism and proNGF mAb might constitute new therapeutic tools to treat or slow down the progression of kidney disease in DM, along with other diabetic related complications. The translational potential of these strategies is currently being investigated.