Abstract
Nephrogenic proteins are re-expressed after ischemia/reperfusion (I/R) injury; however, the role of these proteins is still unknown. We found that sine oculis homeobox 1 (SIX1), a developmentally regulated homeoprotein, is reactivated in tubular epithelial cells after I/R injury associated with cell proliferation/migration and anti-inflammation. We demonstrated that SIX1 promoted cell proliferation by upregulating cyclin and glycolytic genes, and might increase cell migration by upregulating the expression of matrix metalloproteinase 9 (MMP9) directly or indirectly in the cell model. Notably, SIX1 targeted the promoters of the amino-terminal enhancer of split (AES) and fused in sarcoma (FUS), which are cofactors of nuclear factor-κB (NF-κB) subunit RELA, and then inhibited the transactivation function of RELA. The expression of monocyte chemotactic protein-1 (MCP-1) was decreased by the SIX1-mediated NF-κB pathway. Our results showed that the expression of cyclin, glycolytic genes, and MMP9 were significantly increased, and the infiltration of monocytes/macrophages (Mophs) was suppressed in SIX1 overexpression kidney at 1, 2, and 3 days after reperfusion. The overexpression of SIX1 resulted in reducing kidney damage from I/R injury in mice by promoting cell proliferation and migration and by inhibiting inflammation. Our study provides evidence that SIX1 involved in cell proliferation, migration, and anti-inflammation in the I/R model, which might be a potential therapeutic target that could be used to ameliorate kidney damage.
Highlights
The clinical syndrome of acute kidney injury (AKI) is characterized by a rapid fall in the glomerular filtration rate, which frequently leads to chronic kidney disease (CKD), endstage renal disease, and mortality (Thadhani et al, 1996; Coca et al, 2012; Chawla et al, 2014)
The mRNA expression of Six1 was significantly increased in the injured kidney at 1 day (3.6-fold), and peaked at 2 days (7.3-fold), which preceded a significant decrease at 3 days (3.3-fold), but all increased significantly compared with the sham-operated kidney (Figure 1C)
In the I/R injury (IRI) 2 days kidney, Six1+ cells were present in Tubular epithelial cells (TECs), whereas the expression of Six1 was undetectable in the sham-operated kidney (Figures 1E,F)
Summary
The clinical syndrome of acute kidney injury (AKI) is characterized by a rapid fall in the glomerular filtration rate, which frequently leads to chronic kidney disease (CKD), endstage renal disease, and mortality (Thadhani et al, 1996; Coca et al, 2012; Chawla et al, 2014). The surviving TECs dedifferentiate, migrate along the basement membrane, and proliferate to restore cell numbers, which results in the restoration of the functional integrity of the nephron (Humphreys et al, 2008). Molecules such as PAX2 and WNT4, which are expressed in the metanephric mesenchyme during kidney development but not in the mature nephron, are abundantly expressed in TECs after I/R injury (Villanueva et al, 2006; Little and Kairath, 2017; Kumar, 2018). Whether the reactivated genes are involved in cell proliferation and migration in the early stage after I/R injury has remained unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
