Modulation of diabetic kidney disease markers by an antagonist of p75 NTR in streptozotocin-treated mice

Two therapeutic agents targeting p75 pathways have been recently developed to alleviate retinopathy and bladder dysfunction in diabetes mellitus (DM), namely the small molecule p75 antagonist THX-B and a monoclonal antibody (mAb) that neutralizes the receptor ligand proNGF. We herein explore these t...

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Bibliographic Details
Published in:Gene 2022-09, Vol.838, p.146729
Main Authors: Luu, Bryan E, Mossa, Abubakr H, Cammisotto, Philippe G, Uri Saragovi, H, Campeau, Lysanne
Format: Article
Language:English
Subjects:
Animals
Biomarkers
Creatinine
Diabetes Complications
Diabetes Mellitus
Diabetic Nephropathies - drug therapy
Inflammation
Mice
MicroRNAs - genetics
Nerve Growth Factor - metabolism
Receptors, Nerve Growth Factor - antagonists & inhibitors
Streptozocin
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Summary:Two therapeutic agents targeting p75 pathways have been recently developed to alleviate retinopathy and bladder dysfunction in diabetes mellitus (DM), namely the small molecule p75 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 p75 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. P75 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.
ISSN:1879-0038