The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy.

The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients' quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic nephropathy patients. Impaired lipid signaling, especially abnormal protein kinase C (PKC) activation by de novo-synthesized diacylglycerol (DG) under high blood glucose, is one of the causes of diabetic nephropathy. DG kinase (DGK) is an enzyme that phosphorylates DG and generates phosphatidic acid, i.e., DGK can inhibit PKC activation under diabetic conditions. Indeed, it has been proven that DGK activation ameliorates diabetic nephropathy. In this review, we summarize the involvement of PKC and DGK in diabetic nephropathy as therapeutic targets, and its mechanisms, by referring to our recent study.

Clinically Different Presentations of Family Members With the Same Homozygote Diacylglycerol Kinase Epsilon Mutation: Case Report.

Membranoproliferative glomerulonephritis and renal microangiopathies may manifest similar clinical presentations and histology. Many genetic mutations that cause these diseases have been reported. Studies on mutations in the gene encoding diacylglycerol kinase epsilon identified a novel pathophysiologic mechanism leading to atypical hemolytic uremic syndrome and/or membranoproliferative glomerulonephritis. Here, we present the different clinical presentations and treatments in 4 family members who carried the same homozygous diacylglycerol kinase epsilon mutation. The first patient (age 5 years, 3 months old at diagnosis) had nephrotic syndrome. The kidney biopsy was membranoproliferative glomerulonephritis; partial remission was achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil treatment. The second patient (age 5 years, 7 months at diagnosis) presented with overlapping atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis. Remission could not be achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil, and hemodialysis treatment was started. At 10 years from first admission, the patient had end-stage kidney disease, and kidney transplant was performed successfully. The third patient was admitted with the diagnosis of nephrotic syndrome at 13 months of age, kidney biopsy showed membranoproliferative glomerulonephritis, and spontaneous remission developed during followup. He presented with hemolytic uremic syndrome 15 months after the first admission, and dialysis was started. Remission was achieved with plasma infusion and eculizumab treatment. The fourth patient (a 7-month-old boy and brother of patient 3) had no clinical or laboratory findings. All patients had genetic analysis, and mutation in exon 2:c.473G>A(p. W158*) was detected. Our related patients with the same mutation showed different clinical and histological findings. However, we did not observe a clear genotype-phenotype correlation in patients with diacylglycerol kinase epsilon nephropathy, suggesting additional factors mediating phenotypic heterogeneity.

Receptores de feromonas de mamíferos: supervivencia y sexualidad / Mammalian pheromone receptors: survival and sexuality

En 1995 Catherine Dulac y Richard Axel publicaron la existencia de una nueva familia de genes que codificaban los posibles receptores de feromonas, pertenecientes a la amplia familia de los de siete hélices transmembranares y acoplados a proteínas G. Desde entonces se han clonado nuevos genes que han sido agrupados en dos familias, los receptores vomeronasales tipo 1 y 2, V1R y V2R, con diferente estructura y situados con diferente distribución en el órgano vomeronasal. La naturaleza química de las feromonas y de las proteínas que las asocian y transportan conocidas como lipocalinas es otro de los aspectos de los que se dispone de abundante información. Los mecanismos de transducción de la señal mediada por feromonas sobre los receptores V1R y V2R implican la activación de la fosfolipasa C tipo β2, PLCβ2, generando el fosfatidilinositol trifosfato y el diacilglicerol en la cara interna de la membrana neuronal. El diacilglicerol es un ligando endógeno, que permite la apertura del canal de la familia TRPC (Transient Receptor Potential Channel) denominado TRPC2 que se abre y deja pasar iones Ca2+ y Na+ al interior de la neurona sensorial, iniciando la despolarización de la membrana y originando el potencial de acción. La señal eléctrica es conducida al bulbo olfativo auxiliar por axones que llegan de modo disperso y establecen conexión con las células mitrales, las cuales envían sus prolongaciones hasta el sistema límbico y otras estructuras cerebrales, donde influencian o provocan las respuestas de supervivencia de la especie, entre ellas las de apareamiento y agresividad. Un aspecto relevante desde el punto de vista evolutivo es que en primates el gen TRPC2 es un pseudogen sin funcionalidad y por lo tanto el órgano vomeronasal es un vestigio carente de función. Recientes estudios indican que la captación de feromonas en primates se realiza a través del epitelio olfativo y el bulbo olfativo principal e incluso en otros mamíferos esta estructura parece mediar en algunas respuestas especie específicas

In 1995 Catherine Dulac and Richard Axel discovered a new gene family corresponding to the pheromone receptors. They were members of the seven transmembrane helix coupled to G proteins. Since then, new genes have been clonned and grouped according their sequence homology in two main families of vomeronasal receptors the V1R and the V2R. They exhibit different distribution pattern at the vomeronasal epithelium, where they are coupled to different G proteins. The chemical nature of the mammalian pheromones is very diverse and can associate with proteins called lipocalins to reach the vomeronasal organ. The transduction mechanisms of pheromone receptors, V1R and V2R, require respectively a Gi and a Go proteins, to further activate a phospholipase C, the PLCβ2. This enzyme hydrolyses the phosphatidyl inositol located at the plasma membrane originating phosphatidylinositol triphosphate and diacylglycerol. Diacylglycerol is an endogenous ligand that opens the TRPC2 channel (Transient Receptor Potential Channel), allowing the entrance of cations, mostly Ca2+ y Na+. The membrane depolarisation at the vomeronasal neuron originates the action potential that is sent to the accessory olfactory bulb by the axon, which in a different way as those from the main olfactory epithelia, do not organise the axonal prolongations and reach the mitral neurones in a disperse way, without forming a glomerular structure, afterwards the mitral cells send their axons to the limbic system and other cerebral structures related to aggressive behaviour and mating. It is relevant to underline that in monkeys from the old world and primates including humans, the vomeronasal organ is only a vestigial structure without function. The reason relies on the TRPC2 gene, which is a pseudo gene, without physiological function. Recent experimental approaches have demonstrated that the sensing of some pheromonal signals in these species, and also in mammals with a functional vomeronasal organ, can be carried out by the main olfactory epithelia through the main olfactory bulb. This structure being also connected to the hypothalamus, where neurones releasing LHRH can control sexual behaviour. These data confirm the broad possibilities of signalling through pheromones and that much effort is still required to fully understand their possibilities