Mucin-fused myeloid-derived growth factor (MYDGF164) exhibits a prolonged serum half-life and alleviates fibrosis in chronic kidney disease.

Abstract

BACKGROUND AND PURPOSE:

Although no effective therapy is available to stop or reverse CKD progression targeting its key feature, the loss of peritubular capillaries (PTCs) leading to interstitial fibrosis, myeloid-derived growth factor (MYDGF) with tissue-repairing activities enlightens its therapeutic potential for CKD. However, the extremely short circulatory lifetime (15 min) restricts its application.

EXPERIMENTAL APPROACH:

We selected a tandem repeated (TR) region of human CD164 as a carrier to fuse with MYDGF and then investigated for biophysical and pharmacokinetic changes. The MYDGF164 bioactivities were validated in HUVECs and then assessed in HK-2 cells. We also investigated its efficacy in unilateral ureteral obstruction (UUO)-treated mice and in adenine-induced CKD rats.

KEY RESULTS:

MYDGF164 was modified with sialoglycans, improving its resistance to serum proteases and increasing its hydrodynamic radius. The half-life of MYDGF164 was significantly prolonged but retained its original cell proliferation, anti-apoptosis, and tubulogenesis activities. It selectively stimulated the proliferation in endothelial and epithelial cells through phosphorylating MAPK1/3. MYDGF164 alleviated capillary rarefaction, hypoxia, renal fibrosis, and tubular atrophy in UUO mice and in adenine-induced CKD rats. MYDGF164 restored renal function, with normalized creatinine and urea levels in adenine-induced CKD rats. Histopathology and immunohistochemistry revealed that MYDGF164 protection was related to its cell-proliferative, anti-apoptosis, and angiogenesis activities.

CONCLUSIONS AND IMPLICATIONS:

This study is the first successful example of using a tandem repeated region of hCD164 as a cargo protein for the pharmacokinetic improvement of therapeutic proteins. Our findings highlight the potential of MYDGF164 in alleviating renal fibrosis in CKD.

• Authors: Pei Du, Ting Wang, Hang Wang, Meijia Yang, Hongping Yin
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 16 Pg. 4136-4156 (08 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 35393682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The British Pharmacological Society.

Chemical References

• Intercellular Signaling Peptides and Proteins
• Mucins
• Adenine

Topics

• Adenine (pharmacology)
• Animals
• Disease Models, Animal
• Fibrosis
• Half-Life
• Humans
• Intercellular Signaling Peptides and Proteins
• Kidney (pathology)
• Kidney Diseases (metabolism)
• Mice
• Mucins (therapeutic use)
• Rats
• Renal Insufficiency, Chronic (drug therapy)
• Ureteral Obstruction (metabolism)