TY - JOUR
T1 - Endotrophin neutralization through targeted antibody treatment protects from renal fibrosis in a podocyte ablation model
AU - An, Yu A.
AU - Xiong, Wei
AU - Chen, Shiuhwei
AU - Bu, Dawei
AU - Rutkowski, Joseph M.
AU - Berger, Joel P.
AU - Kusminski, Christine M.
AU - Zhang, Ningyan
AU - An, Zhiqiang
AU - Scherer, Philipp E.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - Antibody treatment
KW - Chronic kidney disease
KW - Endotrophin
KW - Podocin
KW - Podocytes
KW - Renal fibrosis
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U2 - 10.1016/j.molmet.2023.101680
DO - 10.1016/j.molmet.2023.101680
M3 - Article
C2 - 36696925
AN - SCOPUS:85147098728
SN - 2212-8778
VL - 69
JO - Molecular Metabolism
JF - Molecular Metabolism
M1 - 101680
ER -