Characterization of aldo-keto reductase 1C subfamily members encoded in two rat genes (akr1c19 and RGD1564865). Relationship to 9-hydroxyprostaglandin dehydrogenase.

Rat genes, akr1c19 and RGD1564865, encode members (R1C19 and 20HSDL, respectively) of the aldo-keto reductase (AKR) 1C subfamily, whose functions, however, remain unknown. Here, we show that recombinant R1C19 and 20HSDL exhibit NAD+-dependent dehydrogenase activity for prostaglandins (PGs) with 9α-hydroxy group (PGF2α, its 13,14-dihydro- and 15-keto derivatives, 9α,11ß-PGF2 and PGD2). 20HSDL oxidized the PGs with much lower Km (0.3-14 µM) and higher kcat/Km values (0.064-2.6 min-1µM-1) than those of R1C19. They also differed in other properties: R1C19, but not 20HSDL, oxidized some 17ß-hydroxysteroids (5ß-androstane-3α,17ß-diol and 5ß-androstan-17ß-ol-3-one). 20HSDL was specifically inhibited by zomepirac, but not by R1C19-selective inhibitors (hexestrol, flavonoids, ibuprofen and flufenamic acid), although the two enzymes were sensitive to indomethacin and cis-unsaturated fatty acids. The mRNA for 20HSDL was expressed abundantly in rat kidney and at low levels in the liver, testis, brain, heart and colon, in contrast to ubiquitous expression of R1C19 mRNA. The comparison of enzymic features of R1C19 and 20HSDL with rat PG dehydrogenases and other AKRs suggests not only a close relationship of 20HSDL with 9-hydroxy-PG dehydrogenase in rat kidney, but also roles of R1C19 and rat AKRs (1C16 and 1C24) in the metabolism of PGF2α, PGD2 and 9α,11ß-PGF2 in other tissues.

Adaptation of the secretome of Echinostoma caproni may contribute to parasite survival in a Th1 milieu.

Echinostoma caproni (Trematoda: Echinostomatidae) is an intestinal trematode, broadly employed to study the host-dependent mechanisms that govern the evolution of intestinal helminth infections. Resistance against E. caproni homologous secondary infections has been reported in mice and appears to be related to the generation of a local Th2 response, whereas Th1 responses promote the development of chronic primary infections. Herein, the ability of E. caproni to modulate its secretome according to the host environment is investigated. A two-dimensional differential in gel electrophoresis (2D-DIGE) analysis was performed to elucidate changes in the excretory/secretory products of E. caproni adults after primary and secondary infections in mice. A total of 16 protein spots showed significant differences between groups, and 7 of them were successfully identified by mass spectrometry. Adult worms exposed to a primary infection appear to upregulate proteins involved in detoxification (aldo-keto reductase), stress response (GroEL), and enhancement of parasite survival (acetyl-CoA A-acetyltransferase and UTP-glucose-1-phosphate urydyltransferase). In contrast, any protein was found to be significantly upregulated after secondary infection. Upregulation of such proteins may serve to withstand the hostile Th1 environment generated in primary infections in mice. These results provide new insights into the resistance mechanisms developed by the parasites to ensure their long-term survival.

Association of Impaired Reactive Aldehyde Metabolism with Delayed Graft Function in Human Kidney Transplantation.

Delayed graft function is an early complication following kidney transplantation with an unclear molecular mechanism. Here we determined whether impaired reactive aldehyde metabolism is associated with delayed graft function. Human kidney biopsies from grafts with delayed graft function were compared with grafts that did not develop delayed graft function by Ingenuity gene pathway analysis. A second series of grafts with delayed graft function (n = 10) were compared to grafts that did not develop delayed graft function (n = 10) by measuring reactive aldehyde metabolism, reactive aldehyde-induced protein adduct formation, and aldehyde dehydrogenase (ALDH) gene and protein expression. In the first series of kidney biopsies, several gene families known for metabolizing reactive aldehydes, such as aldehyde dehydrogenase (ALDH), aldo-keto reductase (AKR), and glutathione-S transferase (GSTA), were upregulated in kidneys that did not develop delayed graft function versus those that did. In the second series of kidney grafts, we focused on measuring aldehyde-induced protein adducts and ALDH enzymatic activity. The reactive aldehyde metabolism by ALDH enzymes was reduced in kidneys with delayed graft function compared to those that did not (37 ± 12∗ vs. 79 ± 5 µg/min/mg tissue, ∗ P < 0.005, respectively). ALDH enzymatic activity was also negatively correlated with length of hospital stay after a kidney transplant. Together, our study identifies a reduced ALDH enzymatic activity with kidneys developing delayed graft function compared to those that did not. Measuring ALDH enzymatic activity and reactive aldehyde-induced protein adducts can potentially be further developed as a biomarker to assess for delayed graft function and recovery from a kidney transplant.