Module 4-Deficient CCN2/Connective Tissue Growth Factor Attenuates the Progression of Renal Fibrosis via Suppression of Focal Adhesion Kinase Phosphorylation in Tubular Epithelial Cells

Hiroaki Amano; Tsutomu Inoue; Takeru Kusano; Daichi Fukaya; Wakako Kosakai; Hirokazu Okada

doi:10.1080/10985549.2023.2253130

Module 4-Deficient CCN2/Connective Tissue Growth Factor Attenuates the Progression of Renal Fibrosis via Suppression of Focal Adhesion Kinase Phosphorylation in Tubular Epithelial Cells

Mol Cell Biol. 2023;43(10):515-530. doi: 10.1080/10985549.2023.2253130. Epub 2023 Oct 11.

Authors

Hiroaki Amano¹, Tsutomu Inoue¹, Takeru Kusano², Daichi Fukaya¹, Wakako Kosakai¹, Hirokazu Okada¹

Affiliations

¹ Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
² General Internal Medicine, Faculty of Medicine, Saitama Medical University, Saitama, Japan.

PMID: 37746701
PMCID: PMC10569360 (available on 2024-09-25)
DOI: 10.1080/10985549.2023.2253130

Abstract

CCN2/connective tissue growth factor (CTGF) potentially serves as a therapeutic target for chronic kidney disease. Here we investigated CCN2 module-4, encoded by Ccn2 exon 5, through the generation of Ccn2 exon 5 knockout mice (Ex5^-/- mice). To investigate renal fibrosis pathogenesis, Ex5^-/- mice were employed to model unilateral ureteral obstruction (UUO), unilateral ischemic-reperfusion injury (UIRI), and 5/6 nephrectomy. Interstitial fibrosis was significantly attenuated in the Ex5^-/- mice in the three models. Furthermore, phosphorylated focal adhesion kinase (FAK) levels in tubular epithelial cells were significantly lower in the kidneys of the UUO- and UIRI-Ex5^-/- mice than those of the Ex5^+/+ mice. Moreover, CCN2 module 4-mediated renal tubule FAK and promoted fibrosis. These findings indicate that CCN2 module-4-FAK pathway components will serve as therapeutic targets for effectively attenuating renal fibrosis.

Keywords: CCN2/CTGF; CKD; Chronic kidney disease; FAK; Focal adhesion kinase; centralized communication network 2; fibrosis.

Grants and funding

This work was supported by research grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology [Grant nos. 25461228, 16K09626, 16K09627 and 19K08731].