HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXR␥. RAR␣ antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RAR␣ is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RAR␣-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.

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BackgroundInsect mitochondrial genomes (mitogenomes) exhibit high diversity in some lineages. The gene rearrangement and large intergenic spacer (IGS) have been reported in several Coleopteran species, although very little is known about mitogenomes of Meloidae.ResultsWe determined complete or nearly complete mitogenomes of seven meloid species. The circular genomes encode 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs) and two ribosomal RNAs (rRNAs), and contain a control region, with gene arrangement identical to the ancestral type for insects. The evolutionary rates of all PCGs indicate that their evolution is based on purifying selection. The comparison of tRNA secondary structures indicates diverse substitution patterns in Meloidae. Remarkably, all mitogenomes of the three studied Hycleus species contain two large intergenic spacers (IGSs). IGS1 is located between trnW and trnC, including a 9 bp consensus motif. IGS2 is located between trnS2 (UCN) and nad1, containing discontinuous repeats of a pentanucleotide motif and two 18-bp repeat units in both ends. To date, IGS2 is found only in genera Hycleus across all published Coleopteran mitogenomes. The duplication/random loss model and slipped-strand mispairing are proposed as evolutionary mechanisms for the two IGSs (IGS1, IGS2). The phylogenetic analyses using MrBayes, RAxML, and PhyloBayes methods based on nucleotide and amino acid datasets of 13 PCGs from all published mitogenomes of Tenebrionoids, consistently recover the monophylies of Meloidae and Tenebrionidae. Within Meloidae, the genus Lytta clusters with Epicauta rather than with Mylabris. Although data collected thus far could not resolve the phylogenetic relationships within Meloidae, this study will assist in future mapping of the Meloidae phylogeny.ConclusionsThis study presents mitogenomes of seven meloid beetles. New mitogenomes retain the genomic architecture of the Coleopteran ancestor, but contain two IGSs in the three studied Hycleus species. Comparative analyses of two IGSs suggest that their evolutionary mechanisms are duplication/random loss model and slipped-strand mispairing.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4102-y) contains supplementary material, which is available to authorized users.

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