BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD.

Abstract

Renal fibrosis is a key pathological phenomenon of chronic kidney disease (CKD) contributing to the progressive loss of renal function. UK383,367 is a procollagen C proteinase inhibitor that has been selected as a candidate for dermal antiscarring agents, whereas its role in renal fibrosis is unclear. In the present study, UK383,367 was applied to a CKD mouse model of unilateral ureteral obstruction (UUO) and cell lines of renal tubular epithelial cells (mouse proximal tubular cells) and renal fibroblast cells (NRK-49F cells) challenged by transforming growth factor-β1. In vivo, bone morphogenetic protein 1, the target of UK383,367, was significantly enhanced in UUO mouse kidneys and renal biopsies from patients with CKD. Strikingly, UK383,367 administration ameliorated tubulointerstitial fibrosis as shown by Masson's trichrome staining in line with the blocked expression of collagen type I/III, fibronectin, and α-smooth muscle actin in the kidneys from UUO mice. Similarly, the enhanced inflammatory factors in obstructed kidneys were also blunted. In vitro, UK383,367 pretreatment inhibited the induction of collagen type I/III, fibronectin, and α-smooth muscle actin in both mouse proximal tubular cells and NRK-49F cells treated with transforming growth factor-β1. Taken together, these findings indicate that the bone morphogenetic protein 1 inhibitor UK383,367 could serve as a potential drug in antagonizing CKD renal fibrosis by acting on the maturation and deposition of collagen and the subsequent profibrotic response and inflammation.

• Authors: Mi Bai, Juan Lei, Shuqin Wang, Dan Ding, Xiaowen Yu, Yan Guo, Shuang Chen, Yang Du, Deyi Li, Yue Zhang, Songming Huang, Zhanjun Jia, Aihua Zhang
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 317 Issue 6 Pg. F1430-F1438 (12 01 2019) ISSN: 1522-1466 [Electronic] United States
• PMID: 31545926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• Collagen Type III
• Fibronectins
• Oxadiazoles
• Renal Agents
• UK-383,367
• Bmp1 protein, mouse
• Bone Morphogenetic Protein 1

Topics

• Animals
• Bone Morphogenetic Protein 1 (antagonists & inhibitors)
• Cell Line
• Child
• Child, Preschool
• Collagen Type I (antagonists & inhibitors, biosynthesis)
• Collagen Type III (antagonists & inhibitors, biosynthesis)
• Female
• Fibronectins (antagonists & inhibitors, biosynthesis)
• Fibrosis (drug therapy)
• Humans
• Inflammation (pathology, prevention & control)
• Kidney (pathology)
• Kidney Function Tests
• Male
• Mice
• Mice, Inbred C57BL
• Oxadiazoles (therapeutic use)
• Renal Agents (therapeutic use)
• Renal Insufficiency, Chronic (complications, drug therapy, pathology)
• Ureteral Obstruction (complications)