NPS-2143 The phenotypes of ESCS Nr e zebrafish
The phenotypes of ESCS, Nr2e3 zebrafish, Nrl mouse and rd7 mouse demonstrate that Nr2e3 has a critical role for rod development in zebrafish and human. By contrast, it is Nrl that modulates rod development in mouse. However, Nrl alone is not sufficient to maintain rod survival in rd7 mouse. Therefore, Nr2e3 may play a role in rod maintenance.
There are two hypotheses that may account for the enhanced S-cones in ESCS and rd7 mouse. One is that lack of Nr2e3 function leads the plastic rod precursors to transdifferentiate into S-cones. Two lines of evidence support this hypothesis: 1) Nr2e3 is predominantly expressed in developing and mature rods and plays a dual role in promoting NPS-2143 of rod genes and repressing cone genes ; 2) there are hybrid rod-cone photoreceptors expressing both rod and cone genes in the rd7 mouse . The second hypothesis is that losing Nr2e3 causes aberrant proliferation of cone progenitors. Observations that Nr2e3 is expressed in cone progenitors and mature cones, as well as the fact that there are no hybrid photoreceptors, support this hypothesis . In zebrafish, we observed Nr2e3 function only in rod lineage; cone development and proliferation of cone progenitors were not changed. Thus, our data contradict the second hypothesis. However, there are remaining questions about the first hypothesis. Rods account for 97% of the number of photoreceptors in the mouse retina, while the S-cones increased only 2-fold in the rd7 retina . This suggests only a small fraction of rod precursors were transformed into S-cones. Because a fraction of rods were derived from the default S-cones in mouse , perhaps it was these rods that reverted back to S-cones when Nrl/Nr2e3 was lost. The enhanced S-cones were actually the default S-cones. By contrast, UV- or S-cone is not the default photoreceptor in zebrafish [10,43] (and the current data). Thus, the number of these two cone types is not increased when rods were lost in Nr2e3 zebrafish.
The mechanism that causes selective L-/M-cone photoreceptor degeneration remains unknown. In ESCS and rd7, arrangement of the ONL was disorganized and this disorganization was present before photoreceptor degeneration [35,64]. Disorganized arrangement of the ONL (especially nuclei of L-/M-cones) was also observed in Nr2e3 zebrafish, which could have led to the degeneration. This disorganization seemed to have little effect on UV- or S-cone survival. Analysis of a 77-year-old postmortem ESCS retina showed that the number of S-cones was maintained . Besides, S-cones can survive normally to 5 months in rd7 mouse and 31 weeks in Nrl mouse [24,35]. UV-and S-cones can survive to 10 months in Nr2e3 zebrafish. It is possible that the interaction between rods and L-/M-cones is more critical than that with UV- or S-cones.
Conflict of interest statement
Introduction Chronic kidney disease (CKD) is currently a worldwide health problem with rising incidence and poor outcomes. It is characterized by the sustained and progressive, decline of glomerular filtration rate, which is conditioned by the excessive accumulation of extracellular matrix (ECM) proteins at the extracellular compartment, both at glomerular and tubule-interstitial levels. The mechanisms responsible for this increased ECM protein synthesis seem to be very complex, but it appears to relay mainly in the tissue inflammation that characterizes some of the renal diseases [1,2], and in the transformation of resident renal cells into matrix producing cells [3,4]. In addition, and concerning specially to the development of tubule-interstitial fibrosis, some authors propose that the transformation of renal epithelial and endothelial cells toward a mesenchymal state, through the epithelial-to-mesenchymal (EMT) or endothelial-to-mesenchymal transition process, may also contribute to ECM deposition in the extracellular compartment [5,6]. As these mechanisms have not been definitely demonstrated, it has been also suggested that tubular epithelial cells would relay signals to the underlying interstitial compartment, thus promoting myofibroblast differentiation and immune cells recruitment with the subsequently increased fibrogenesis and inflammation [, , ].