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Diabetic retinopathy (DR) is the most common complication that develops in patients with diabetes mellitus (DM) and is the leading cause of blindness worldwide. Fortunately, sight-threatening forms of DR develop only after several decades of DM. This well-documented resilience to DR suggests that the retina is capable of protecting itself from DM-related damage and also that accumulation of such damage occurs only after deterioration of this resilience. Despite the enormous translational significance of this phenomenon, very little is known regarding the nature of resilience to DR. Rodent models of DR have been used extensively to study the nature of the DM-induced damage, i.e., cardinal features of DR. Many of these same animal models can be used to investigate resilience because DR is delayed from the onset of DM by several weeks or months. The purpose of this review is to provide a comprehensive overview of the literature describing the use of rodent models of DR in type-1 and type-2 diabetic animals, which most clearly document the delay between the onset of DM and the appearance of DR. These readily available experimental settings can be used to advance our current understanding of resilience to DR and thereby identify biomarkers and targets for novel, prevention-based approaches to manage patients at risk for developing DR. [ABSTRACT FROM AUTHOR]

Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor α (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFR α conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFR α-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFR α that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFR α-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFR α, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFR α and PDGF-A are coexpressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFR α promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas., Introduction Human gliomas account for the most common and malignant tumors in the CNS (1). Despite intensive treatments including maximal surgical resection, combined with radiotherapy and concurrent or adjuvant chemotherapies, [...]

PDGF B chain or PDGF receptor (PDGFR)-[beta]-deficient (-/-) mice lack mesangial cells. To study responses of [alpha]- and [beta]-receptor activation to PDGF ligands, metanephric mesenchymal cells (MMCs) were established from embryonic day E11.5 wild-type (+/+) and -/- mouse embryos. PDGF BB stimulated cell migration in +/+ cells, whereas PDGF AA did not. Conversely, PDGF AA was chemotactic for -/- MMCs. The mechanism by which PDGFR-[beta] inhibited AA-induced migration was investigated. PDGF BB, but not PDGF AA, increased intracellular [Ca.sup.2+] and the production of reactive oxygen species (ROS) in +/+ cells. Transfection of -/- MMCs with the wild-type [beta]-receptor restored cell migration and ROS generation in response to PDGF BB and inhibited AA-induced migration. Inhibition of [Ca.sup.2+] signaling facilitated PDGF AA-induced chemotaxis in the wild-type cells. The antioxidant N-acetyl-L-cysteine (NAC) or the NADPH oxidase inhibitor diphenyleneiodonium (DPI) abolished the BB-induced increase in intracellular [Ca.sup.2+] concentration, suggesting that ROS act as upstream mediators of [Ca.sup.2+] in suppressing PDGF AA-induced migration. These data indicate that ROS and [Ca.sup.2+] generated by active PDGFR-[beta] play an essential role in suppressing PDGF AA-induced migration in +/+ MMCs During kidney development, PDGFR [beta]-mediated ROS generation and [Ca.sup.2+] influx suppress PDGF AA-induced chemotaxis in metanephric mesenchyme. reactive oxygen species; calcium