Increased expression of the proton-sensing G protein-coupled receptor Gpr65 during retinal degeneration.

The retina is a metabolically highly active tissue that is sensitive to pH changes. Blinding diseases of the retina are often characterized by degeneration of photoreceptor cells altering the acid-base homeostasis of the tissue microenvironment and by an accompanying inflammatory response. GPR4, GPR65 and GPR68 are G protein-coupled receptors that aid cells to sense and survive conditions of acidic pH and inflammatory cells express Gpr65 enhancing their viability. Hence, we investigated expression and function of these proton-sensing GPRs in the normal and degenerating retina. We observed increased retinal expression of Gpr65, but not of Gpr4 and Gpr68, in mouse models of both inherited (rd10) and induced (light damage) retinal degeneration. Lack of GPR65 slightly accelerated photoreceptor degeneration in rd10 mice and resulted in a strong activation of microglia after light-injury. Since GPR65 was dispensable for normal retinal development, function and aging as evidenced by the evaluation of Gpr65(-/-) mice, our results indicate that the proton-sensing G protein-coupled receptor GPR65 may be involved in a mechanism that supports survival of photoreceptors in the degenerating retina.

Clinical and laboratory markers of autosomal dominant polycystic kidney disease (ADPKD) progression: an overview.

Autosomal dominant polycystic kidney (ADPKD) is the most common inherited renal cystic disease and it occurs in all races, the reported prevalence is between 1:400 and 1:1000. It is characterized by development of cysts in both kidneys and progressive renal function loss. Among most Autosomal Dominant Polycystic Kidney patients, renal function remains intact until the fourth decade of life. It is very important to identify early markers of disease progression to recognize patients with a worse prognosis. The aim of this study is to review the clinical and laboratory markers of ADPKD progression. The early clinical parameters evaluated seem to be directly correlated with the volume of the cysts that determine the kidney volume. From a clinical point of view, total kidney volume (TKV) appears to be the best marker of early ADPKD progression. This review evaluated several ADPKD progression markers comparing the early consolidated clinical and the new promising laboratory indicators. From a laboratory point of view, copeptin has a potential role between the serum biomarkers of ADPKD progression. However, further studies are necessary to validate the potential predictive value of its serum level and to adopt it for routine use. The combination of biomarkers could probably predict ADPKD progression with more accuracy than the use of a single biomarker.

p38 MAPK signaling acts upstream of LIF-dependent neuroprotection during photoreceptor degeneration.

In many blinding diseases of the retina, loss of function and thus severe visual impairment results from apoptotic cell death of damaged photoreceptors. In an attempt to survive, injured photoreceptors generate survival signals to induce intercellular protective mechanisms that eventually may rescue photoreceptors from entering an apoptotic death pathway. One such endogenous survival pathway is controlled by leukemia inhibitory factor (LIF), which is produced by a subset of Muller glia cells in response to photoreceptor injury. In the absence of LIF, survival components are not activated and photoreceptor degeneration is accelerated. Although LIF is a crucial factor for photoreceptor survival, the detailed mechanism of its induction in the retina has not been elucidated. Here, we show that administration of tumor necrosis factor-alpha (TNF) was sufficient to fully upregulate Lif expression in Muller cells in vitro and the retina in vivo. Increased Lif expression depended on p38 mitogen-activated protein kinase (MAPK) since inhibition of its activity abolished Lif expression in vitro and in vivo. Inhibition of p38 MAPK activity reduced the Lif expression also in the model of light-induced retinal degeneration and resulted in increased cell death in the light-exposed retina. Thus, expression of Lif in the injured retina and activation of the endogenous survival pathway involve signaling through p38 MAPK.

Intrinsically photosensitive retinal ganglion cells are resistant to N-methyl-D-aspartic acid excitotoxicity.

PURPOSE: Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin (OPN4) and are mainly responsible for non-image-forming visual tasks such as circadian photoentrainment and the pupillary light reflex. Compared to other classes of RGCs, ipRGCs are more resistant to cell death in several experimental models such as ocular hypertension, optic nerve transection, and others. Here, we tested whether ipRGCs are also resistant to N-methyl-D-aspartic acid (NMDA)-induced excitotoxicity. METHODS: Mice were injected intravitreally with NMDA, and subsequent expression levels of Opn4 and Brn3a mRNA were analyzed with semiquantitative real-time PCR. Cells immunopositive for BRN3A and OPN4 were quantified in retinal flat mounts of NMDA- and PBS-injected eyes. The molecular response of the retina to NMDA treatment was analyzed with real-time PCR and western blotting. Intravitreal injections of wortmannin and AG-490 were used to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, respectively. RESULTS: In contrast to retinal Brn3a expression and BRN3A-containing cells, levels of Opn4 mRNA and the number of OPN4-expressing cells were not reduced after NMDA injection. Survival of ipRGCs after NMDA injection was not strain specific, did not require the presence of photoreceptor cells, and did not depend on PI3K/AKT or JAK/STAT signaling, although both signaling pathways were activated after NMDA treatment. CONCLUSIONS: Our data support the existence of an efficient survival system for ipRGCs. This system does not depend on PI3K/AKT or JAK/STAT signaling. Identification of the responsible molecular survival mechanisms may provide clues to protect "traditional" ganglion cells in diseases such as glaucoma.

[Functional respiratory and blood gas analytical studies of the effects of fenspiride, in oral and intramuscular administration, in chronic bronchopneumopathic subjects]. / Rilievi funzionali respiratori ed emogasanalitici sugli effetti della fenspiride per via orale ed intramuscolare in soggetti broncopneumopatici cronici.

A group of 20 chronic bronchopneumopathics was treated for 15 days with fenspiride orally and i.m. The behaviour of a set of functional respiratory and haemogasanalytic parameters was monitored at various times (basic, 5th, 10th and 15th days). Progressive, significant improvements in VC, FEV1, RV and in related parameters were observed. These were attributed to the drug's anti-inflammatory effect in the respiratory ways as well as to its direct antibronchospastic action. Stress is laid on the excellent clinical tolerance of fenspiride following its oral and i.m. administration.