tretinoin and Diabetic-Retinopathy

Retinoic acid (RA), an active metabolite of vitamin A, is a critical signaling molecule in various cell types. We found that RA depletion caused by expression of the RA-metabolizing enzyme CYP26A1 promotes carcinogenesis, implicating CYP26A1 as a candidate oncogene. Several studies of CYP26s have suggested that the biological effect of RA on target cells is primarily determined by "cellular RA bioavailability", which is defined as the RA level in an individual cell, rather than by the serum concentration of RA. Consistently, stellate cells store approximately 80% of vitamin A in the body, and the state of cellular RA bioavailability regulates their function. Based on the similarities between stellate cells and astrocytes, we demonstrated that retinal astrocytes regulate tight junction-based endothelial integrity in a paracrine manner. Since diabetic retinopathy is characterized by increased vascular permeability in its early pathogenesis, RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness. RA also attenuated the loss of the epithelial barrier in murine experimental colitis. The concept of "cellular RA bioavailability" in various diseases will be directed at understanding various pathologies caused by RA insufficiency, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system.

Topics: Animals; Astrocytes; Biological Availability; Capillary Permeability; Carcinogenesis; Colitis; Diabetic Retinopathy; Endothelial Cells; Female; Humans; Mice; Retina; Retinoic Acid 4-Hydroxylase; Squamous Intraepithelial Lesions of the Cervix; Tight Junctions; Tretinoin

Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes, and a common cause of blindness in working‑age individuals. Mesenchymal stem cell (MSC) transplantation has been considered a promising intervention therapy for DR, wherein the differentiation of MSCs into nerve cells plays an essential role. However, research into the role of MSCs in DR treatment remains incomplete, and the mechanisms of retinal repair at the molecular level have yet to be clarified. In the present study, all‑trans retinoic acid (ATRA) was used to promote the proliferation of rat umbilical cord (UC)‑derived MSCs and their differentiation into nerve cells. Furthermore, the effects and mechanisms of UC‑MSCs with or without ATRA treatment were investigated in rats subjected to streptozocin (STZ)‑induced DR. The results demonstrated that the transplantation of UC‑MSCs treated with or without ATRA attenuated DR in rats, and alleviated retinal tissue damage and apoptosis. In addition, the transplantation of UC‑MSCs treated with or without ATRA attenuated angiogenesis and inflammation in the retina by regulating the levels of relevant cytokines. UC‑MSCs treated with ATRA exerted a more prominent therapeutic effect than the untreated UC‑MSCs. On the whole, these findings indicate that UC‑MSCs alleviate STZ‑induced DR in rats by regulating angiogenesis and the inflammatory response at the molecular level. Thus, the findings of the present study may provide a theoretical basis for the application of MSCs in the treatment of DR.

Topics: Animals; Blotting, Western; Cell Differentiation; Cell Proliferation; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Humans; In Situ Nick-End Labeling; Male; Mesenchymal Stem Cells; Pregnancy; Rats; Streptozocin; Tretinoin; Umbilical Cord

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. But few efficient therapeutic methods have been reported. This study discussed the functions of 9-cis-retinoic acid (9-cis-RA) in sensitizing retinal pericytes to platelet-derived growth factor (PDGF)-BB. Using streptozotocin (STZ)-induced diabetic mice and high glucose-treated bovine retinal pericytes (BRPC), we analyzed the impacts of 9-cis-RA by detecting cell apoptosis via DNA fragmentation assay and detecting related factors through adenovirus or lentivirus infection and western blot. Results showed that in retinas of STZ-induced diabetic mice, 9-cis-RA significantly inhibited expression of SHP-1 (P < 0.01), thus promoting p-AKT and p-ERK1/2, which reflected the improved sensitivity to PDGF-BB. In BRPC, 9-cis-RA also improved sensitivity to PDGF-BB and suppressed cell apoptosis (P < 0.01) via down-regulating SHP-1. Further mechanism analyses showed that the efficient functioning of 9-cis-RA relied on the existence of its receptor, retinoic X receptor α (RXRα), independent of the previous reported protein kinase C delta (PKCδ)/SHP-1 axis. Because 9-cis-RA could not inhibit SHP-1 or improve sensitivity to PDGF-BB when RXRα was knocked down, while it still suppressed SHP-1 after overexpression of PKCδ. Taken together, these results indicated the vital roles of 9-cis-RA in improving sensitivity to PDGF-BB of retinal pericytes in DR, and provided basic evidences of new therapeutic targets like RXRα for further DR treatment.

Topics: Alitretinoin; Animals; Apoptosis; Becaplermin; Cattle; Cells, Cultured; Diabetic Retinopathy; Glucose; Male; Mice; Mice, Inbred C57BL; Pericytes; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Proto-Oncogene Proteins c-sis; Retina; Retinoid X Receptor alpha; RNA, Small Interfering; Tretinoin