| First Author | Matoba K | Year | 2014 |
| Journal | Am J Physiol Renal Physiol | Volume | 307 |
| Issue | 5 | Pages | F571-80 |
| PubMed ID | 25007875 | Mgi Jnum | J:214236 |
| Mgi Id | MGI:5588608 | Doi | 10.1152/ajprenal.00113.2014 |
| Citation | Matoba K, et al. (2014) Rho-kinase regulation of TNF-alpha-induced nuclear translocation of NF-kappaB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells. Am J Physiol Renal Physiol 307(5):F571-80 |
| abstractText | The small GTPase Rho and its downstream effector, Rho-associated coiled-coil containing protein kinase (Rho-kinase), regulate a number of cellular processes, including organization of the actin cytoskeleton, cell adhesion, and migration. While pharmacological inhibitors of Rho-kinase signaling are known to block renal inflammation, the molecular basis for this effect is unclear. Here, we provide evidence that proinflammatory TNF-alpha promotes mesangial expression of macrophage colony-stimulating factor (M-CSF), a key regulator for the growth and differentiation of mononuclear phagocytes, in a Rho-kinase-dependent manner. Consistent with this observation, TNF-alpha-mediated renal expression of M-CSF in insulin-resistant db/db mice was downregulated by Rho-kinase inhibition. Small interfering RNA-facilitated knockdown of Rho-kinase isoforms ROCK1 and ROCK2 indicated that both isoforms make comparable contributions to regulation of M-CSF expression in mesangial cells. From a mechanistic standpoint, Western blotting and EMSA showed that Rho-kinase and its downstream target p38 MAPK regulate nuclear translocation of NF-kappaB RelA/p65 and subsequent DNA binding activity, with no significant effects on IkappaBalpha degradation and RelA/p65 phosphorylation. Moreover, we showed that Rho-kinase-mediated cytoskeletal organization is required for the nuclear uptake of RelA/p65. Collectively, these findings identify Rho-kinase as a critical regulator of chemokine expression and macrophage proliferation. |
