Bases moleculares e celulares das nefropatias hereditárias císticas

The inherited cystic nephropathies (ICNs) are caused by gene mutations determinant to the development of renal epithelial cell abnormalities, alterations that create the biological conditions necessary to cyst formation. The identification of genes mutated in these diseases and the characterization of their protein products have been allowing the elucidation of mechanisms involved in their pathogenesis. The current review focus on the genetic basis and molecular pathogenesis of such illnesses, though it also briefly addresses clinical and epidemiological aspects of the ICNs with higher medical and socioeconomical impact. Within this disease set, we will approach autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, nephronophthises, autosomal dominant tubule-interstitial kidney disease, von Hippel-Lindau disease, and tuberous sclerosis complex. These ICNs present overlapping of clinical manifestations and share pathways and molecular defects. Among their common features, we will focus on the central role of abnormalities affecting the primary apical cilium and intracellular signaling pathways responsible for fundamental alterations in cell phenotype. When highlighting the advances in molecular and cellular pathogenesis of ICNs, we will critically discuss the establishment, the roles and the implications of the defective cytosolic calcium homeostasis; hyperproliferative cell response to cyclic AMP; high cell proliferation and apoptosis rates; extracellular matrix alterations; cell polarity abnormalities; and transepithelial fluid secretion. The knowledge accumulated in the last two decades brought a new molecular and cellular scenario to the ICNs, creating the required platform to develop preclinical assays. Such studies, in turn, have been supporting the performance of robust clinical trials which have been opening promising therapeutic perspectives.As nefropatias hereditárias císticas (NHCs) são causadas por mutações gênicas determinantes ao desenvolvimento de anormalidades nas células renais epiteliais, alterações que criam as condições biológicas necessárias à formação cística. A identificação de genes mutados nessas enfermidades e a caracterização de seus produtos proteicos vêm permitindo a elucidação de mecanismos envolvidos em sua patogênese. Esta revisão tem como foco as bases genéticas e a patogênese molecular dessas enfermidades, embora também aborde brevemente aspectos clínicos e epidemiológicos das NHCs de maior impacto médico e socioeconômico. Dentro deste conjunto de moléstias, abordaremos a doença renal policística autossômica dominante, doença renal policística autossômica recessiva, nefronoftises, doença renal túbulo-intersticial autossômica dominante, doença de von Hippel-Lindau e complexo esclerose tuberosa. Essas NHCs possuem sobreposição de manifestações clínicas e compartilham vias e defeitos moleculares. Entre suas características comuns, destacaremos o papel central de anormalidades no cílio apical primário e de vias de sinalização intracelular responsáveis por alterações fundamentais do fenótipo celular. Ao apresentar os avanços obtidos na patogênese molecular e celular das NHCs, discutiremos criticamente o estabelecimento, os papeis e as implicações da homeostase defeituosa de cálcio citosólico; resposta celular hiperproliferativa ao AMP cíclico; taxas elevadas de proliferação celular e apoptose; alterações da matriz extracelular; alterações da polaridade celular; e secreção transepitelial de fluido. O conhecimento acumulado nas últimas duas décadas trouxe um novo contexto molecular e celular às NHCs, capaz de criar a plataforma de conhecimento necessária para o desenvolvimento de ensaios pré-clínicos. Tais ensaios, por sua vez, vêm amparando a condução de estudos clínicos robustos, os quais têm aberto perspectivas terapêuticas promissoras

Changes in PGC-1α-Dependent Mitochondrial Biogenesis Are Associated with Inflexible Hepatic Energy Metabolism in the Offspring Born to Dexamethasone-Treated Mothers

In the present study we investigated the participation of hepatic peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in the metabolic programming of newborn rats exposed in utero to dexamethasone (DEX). On the 21st day of life, fasted offspring born to DEX-treated mothers displayed increased conversion of pyruvate into glucose with simultaneous upregulation of PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). Increased oxidative phosphorylation, higher ATP/ADP ratio and mitochondrial biogenesis and lower pyruvate levels were also found in the progeny of DEX-treated mothers. On the other hand, the 21-day-old progeny of DEX-treated mothers had increased hepatic triglycerides (TAG) and lower CPT-1 activity when subjected to short-term fasting. At the mechanistic level, rats exposed in utero to DEX exhibited increased hepatic PGC-1α protein content with lower miR-29a-c expression. Increased PGC-1α content was concurrent with increased association to HNF-4α and NRF1 and reduced PPARα expression. The data presented herein reveal that changes in the transcription machinery in neonatal liver of rats born to DEX-treated mothers leads to an inflexible metabolic response to fasting. Such programming is hallmarked by increased oxidative phosphorylation of pyruvate with impaired FFA oxidation and hepatic TAG accumulation.</jats:p

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Cardiac dysfunction in Pkd1 deficient mice is associated with metabolic rewiring, inflammation and apoptosis

Manifestações cardiovasculares são responsáveis por morbidade e mortalidade significativas na doença renal policística autossômica dominante (DRPAD). Associação entre cardiomiopatia dilatada idiopática e DRPAD, assim como um papel primário da deficiência de Pkd1 e Pkd2 nessa disfunção, foram recentemente descritos. Os mecanismos envolvidos na patogênese desse fenótipo, contudo, permanecem amplamente desconhecidos. Nesse cenário, o objetivo deste estudo foi investigar as bases metabólicas e celulares do fenótipo cardíaco associado à DRPAD. Para tanto, utilizamos como modelo experimental camundongos homozigotos para um alelo hipomórfico de Pkd1 (Pkd1V/V, VV), animais que apresentam disfunção cardíaca precocemente. Os corações de camundongos VV não desenvolveram hipertrofia, mas apresentaram apoptose e inflamação aumentadas em comparação a seus respectivos controles selvagens (WT). A expressão dos genes fetais Nppa e Acta1 mostrou-se aumentada em tecido cardíaco VV, revelando uma transição inadequada do perfil transcricional fetal para o perfil pós-natal. Corações VV apresentaram diminuição da expressão de PparAlfa, Pgc1Alfa/PGC1, AMPK total e fosforilada e ACCBeta fosforilada, resultados associados a diminuição da fosforilação oxidativa de ácidos graxos e aumento da oxidação de glicose. Diferentemente de resultados prévios obtidos em rins deficientes em Pkd1, corações VV apresentaram diminuição da atividade de mTORC1, a glicose não foi preferencialmente direcionada para glicólise aeróbica e a concentração de glutamina mostrou-se aumentada quando comparada à dos controles WT. Tais achados acompanharam-se de alterações mitocondriais, incluindo aumento da densidade volumétrica citoplasmática, aumento de fragmentação e aumento do consumo de oxigênio em resposta à glicose. Experimentos de ressonância magnética nuclear identificaram um perfil metabólico distinto em corações VV, caracterizado principalmente por diminuição dos níveis de glicose e aminoácidos (serina, alanina, tirosina, valina, prolina, metionina, glutamato, glicina, aspartato, isoleucina e histidina). Esses dados sugerem que glicose e aminoácidos possam estar sendo utilizados como substrato energético e, possivelmente, para sustentar a biossíntese de compostos envolvidos no metabolismo lipídico e no estresse oxidativo. Nossos achados consistem na primeira descrição de reprogramação metabólica cardíaca associada a deficiência de Pkd1, revelando aspectos comuns e diferentes dos descritos para rins com DRPAD. Nossos resultados constituem, portanto, um marco conceitual na elucidação da patogênese da disfunção cardíaca associada à deficiência de Pkd1, achados provavelmente aplicáveis ao fenótipo cardíaco na DRPAD humanaCardiovascular manifestations account for significant morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD). Association between idiopathic dilated cardiomyopathy and ADPKD as well as a primary role for Pkd1 and Pkd2 deficiency in this dysfunction have been recently described, however the pathogenic mechanisms remain largely unknown. In this scenario, the aim of this study was to investigate the metabolic and cellular basis of ADPKD-associated cardiac phenotype. We used a mouse homozygous for a Pkd1 hypomorphic allele (Pkd1V/V, VV) with early cardiac dysfunction as our experimental model. Dysfunctional VV hearts were not hypertrophic but displayed increased apoptosis and inflammation compared to wild-type controls. Expression of Nppa and Acta1 was increased in VV cardiac tissue, revealing inappropriate transcriptional transition to the mature state. Downregulation of PparAlpha, Pgc1Alpha/PGC1, total and phosphorylated AMPK and phosphorylated ACCBeta, in turn, was associated with abnormal lipid metabolism and increased glucose oxidation. Unlike Pkd1-deficient kidneys, mTORC1 is downregulated, glucose is not targeted for aerobic glycolysis and glutamine is increased in VV hearts. Such findings were accompanied by increased mitochondrial density with decreased size and increased oxygen consumption in response to glucose. NMR experiments identified a distinct metabolite profile in VV hearts, associated with decreased levels of glucose and amino acids (serine, alanine, tyrosine, valine, proline, methionine, glutamate, glycine, aspartate, isoleucine and histidine). These data suggest that glucose and amino acids may be used as energetic substrate and to sustain biosynthesis of metabolites likely involved in lipid metabolism and oxidative stress. Our findings are the first description of cardiac metabolic rewiring associated with Pkd1 deficiency, revealing a pattern just partially similar to the metabolic profile previously observed in the cystic kidney phenotype. Our results constitute, therefore, a conceptual marker in the elucidation of the heart dysfunction pathogenesis associated with Pkd1 deficiency, findings likely applicable to the cardiac phenotype in human ADPK

Contributions of genetically-modified animal models to the understanding and intervention in autosomal dominant polycystic kidney disease: present and future

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease, representing the fourth cause of end-stage kidney disease. This disorder occurs due to mutations in the PKD1 (Polycystic Kidney Disease 1) or PKD2 (Polycystic Kidney Disease 2) genes, with most of the cases caused by mutations in PKD1. The products of these genes, polycystin-1 (PC1) and polycystin-2 (PC2), are integral membrane glycoproteins that form a complex expressed in the surface of primary apical cilia of several cells, including renal tubular cells. Such proteins are also expressed in other subcellular sites. PC2 functions as a non-selective cation channel with high permeability to calcium, while PC1 is thought to function as a membrane receptor and likely as an adhesion molecule. Since the discovery and characterization of PKD1 and PKD2, the generation of genetically-modified animal models has prompted remarkable advances in the elucidation of ADPKD pathogenesis and identification of potential therapeutic targets. Such animals included knockout, knockin and spatial and temporal conditional knockout models. These progresses allowed the recognition of a complex genetic network involved in the modulation of polycystic kidney disease and the identification of potential modifiers of ADPKD. The mentioned advances also allowed the performance of strategic preclinical studies in mouse models orthologous to this disease, creating appropriate platforms to support robust clinical trials. The generation of composed mutants will likely lead to progressively more complex and specific analyses of ADPKD pathogenesis in the next decades, with meaningful clinical consequences. Moreover, the technical complexity and speed of generating strategic genetically-modified animal models has dramatically improved in recent years, considerably expanding the possibilities for the coming future. In addition, recently developed in vitro approaches such as induced pluripotent stem cells, kidney-on-a-chip and kidney organoid technologies are thought to bring robust and complementary future inputs to the understanding and therapy directed to ADPKD