| First Author | Hu Q | Year | 2023 |
| Journal | Int J Mol Sci | Volume | 24 |
| Issue | 4 | PubMed ID | 36834937 |
| Mgi Jnum | J:352284 | Mgi Id | MGI:7441119 |
| Doi | 10.3390/ijms24043504 | Citation | Hu Q, et al. (2023) Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis. Int J Mol Sci 24(4) |
| abstractText | Nephronophthisis (NPHP) is the most prevalent monogenic disease leading to end-stage renal failure in childhood. RhoA activation is involved in NPHP pathogenesis. This study explored the role of the RhoA activator guanine nucleotide exchange factor (GEF)-H1 in NPHP pathogenesis. We analyzed the expression and distribution of GEF-H1 in NPHP1 knockout (NPHP1(KO)) mice using Western blotting and immunofluorescence, followed by GEF-H1 knockdown. Immunofluorescence and renal histology were used to examine the cysts, inflammation, and fibrosis. A RhoA GTPase activation assay and Western blotting were used to detect the expression of downstream GTP-RhoA and p-MLC2, respectively. In NPHP1 knockdown (NPHP1(KD)) human kidney proximal tubular cells (HK2 cells), we detected the expressions of E-cadherin and alpha-smooth muscle actin (alpha-SMA). In vivo, increased expression and redistribution of GEF-H1, and higher levels of GTP-RhoA and p-MLC2 in renal tissue of NPHP1(KO) mice were observed, together with renal cysts, fibrosis, and inflammation. These changes were alleviated by GEF-H1 knockdown. In vitro, the expression of GEF-H1 and activation of RhoA were also increased, with increased expression of alpha-SMA and decreased E-cadherin. GEF-H1 knockdown reversed these changes in NPHP1(KD) HK2 cells. Thus, the GEF-H1/RhoA/MLC2 axis is activated in NPHP1 defects and may play a pivotal role in NPHP pathogenesis. |
