Endotrophin neutralization through targeted antibody treatment protects from renal fibrosis in a podocyte ablation model

Objective: Renal fibrosis is a hallmark for chronic kidney disease (CKD), and often leads to end stage renal disease (ESRD). However, limited interventions are available clinically to ameliorate or reverse renal fibrosis. Methods: Herein, we evaluated whether blockade of endotrophin through neutralizing antibodies protects from renal fibrosis in the podocyte insult model (the POD-ATTAC mouse). We determined the therapeutic effects of endotrophin targeted antibody through assessing renal function, renal inflammation and fibrosis at histological and transcriptional levels, and podocyte regeneration. Results: We demonstrated that neutralizing endotrophin antibody treatment significantly ameliorates renal fibrosis at the transcriptional, morphological, and functional levels. In the antibody treatment group, expression of pro-inflammatory and pro-fibrotic genes was significantly reduced, normal renal structures were restored, collagen deposition was decreased, and proteinuria and renal function were improved. We further performed a lineage tracing study confirming that podocytes regenerate as de novo podocytes upon injury and loss, and blockade of endotrophin efficiently enhances podocyte-specific marker expressions. Conclusion: Combined, we provide pre-clinical evidence supporting neutralizing endotrophin as a promising therapy for intervening with renal fibrosis in CKD, and potentially in other chronic fibro-inflammatory diseases. o 2023 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study demonstrates that neutralizing endotrophin antibody treatment can effectively alleviate renal fibrosis, improving transcriptional, morphological, and functional levels. It restores normal renal structures, decreases collagen deposition, and improves proteinuria and renal function. The study also confirms that neutralizing endotrophin enhances podocyte regeneration. Overall, this pre-clinical evidence supports neutralizing endotrophin as a potential therapy for chronic kidney disease-related renal fibrosis.