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  • AZD-5991 Our in vivo model confirmed the

    2019-07-08

    Our in vivo model confirmed the key role of ILK during the pathogenesis of some forms of renal diseases [17,22], but we explained some of the mechanisms involved in this process and verified for the first time that ILK blockade in the CKD early stages may stop the pathophysiological process that leads to the progression of renal disease to end-stage renal failure, which emphasizes great potential applications in clinical practice. Additional studies must be performed to determine whether these events are significant in some renal diseases or if they may be considered a mechanism of progression of renal damage. The following are the supplementary data related to this article.
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    Introduction Brown adipose tissue (BAT) is specialized in the generation of heat to maintain body temperature in response to cold through a process known as non-shivering adaptive thermogenesis [1]. The thermogenic activity of BAT depends on the exclusive expression in brown adipocytes of UCP1, a protein located in the inner membrane of mitochondria that functions as a proton channel and uncouples substrate oxidation (i.e. fatty acids and glucose) from the synthesis of ATP. As a result, the energy accumulated as an electrochemical gradient generated by the respiratory chain is dissipated as heat [2]. In addition to brown adipocytes located in BAT depots, brown-like adipocytes can be also found interspersed within white adipose tissue (WAT) [3,4]. These so-called “brite” or “beige” adipocytes, which are ontogenically distinct from “classical” brown adipocytes of BAT [5], express UCP1 in sufficient amounts to become thermogenically competent [6]. Increased occurrence and thermogenic activity of both brown and beige adipocytes have been shown to protect against obesity and metabolic disease in a variety of rodent models (reviewed in [7]). Interestingly, low BAT mass and activity in adult humans have been associated with increased adiposity and high fasting glucose levels, suggesting that defective BAT-dependent thermogenesis could contribute to the development of obesity and/or type 2 diabetes [8,9]. Given its capacity to influence whole body energy and glucose homeostasis, BAT is nowadays viewed as a promising target for the treatment of metabolic diseases. Unlike white adipocytes, which show low mitochondrial mass and limited oxidative capacity, the thermogenic function of brown and beige adipocytes relies on the presence of a vast mitochondrial network. Although subjected to dynamic changes in response to nutritional and environmental cues, the mitochondrial population of brown adipocytes is acquired during the maturation of BAT at late fetal stages in the absence of thermogenic stress or as the result of the differentiation of precursor AZD-5991 in response to thermogenic stimuli [10,11]. The generation of new mitochondria is a complex process that requires the coordinated expression of hundred of genes encoded by two compartmentalized genomes: the nuclear (nDNA) and the mitochondrial (mtDNA) genomes. Mitochondrial biogenesis in BAT has been shown to be tightly controlled at the transcriptional level by set of key transcription factors that include NRF-2/GABP [12], ERRα/γ [13,14] and the transcriptional co-activators PGC-1α and β [10,15,16], all of which directly control the expression of nDNA-encoded mitochondrial genes. Less is known about how the expression of mtDNA-encoded genes is controlled in brown adipocytes. Mitochondrial transcription factors TFAM and TFB2M are known to coordinate the transcription of the mtDNA genes in several cell types and tissues (reviewed in [17]), but detailed information about their specific functional relevance in BAT is still missing. The MTERF (mitochondrial transcription termination factor) family of proteins, that include MTERF1, 2, 3 and 4, constitute, from the functional point of view, a heterogeneous group of mitochondrial factors whose function in the control of the expression of mtDNA-encoded genes remains to be fully elucidated. MTERF1, the founding member of the family, was described as a terminator of the transcription of the mtDNA H-strand [18]. However, more recent studies suggest that MTERF1 only acts as a partial terminator of H-strand transcription whereas it completely terminates L-strand transcription as a way to prevent the antisense transcription of the ribosomal RNA genes [18]. The function of MTERF2 remains completely unknown, although it has been suggested that it could work as a positive regulator of mtDNA transcription [19]. Contrarily, MTERF3 has been described as a repressor of mtDNA transcription [20]. Still, others studies have suggested that MTERF3 could be involved in the control of mitochondrial protein translation by participating in the assembly of the large mitochondrial ribosomal subunit through its interaction with the 16S rRNA [21]. Contrarily to MTERF2 and 3, no direct role in mtDNA transcription or replication has been attributed to MTERF4. Instead, the most recent studies suggest that MTERF4 participates in the assembly of mitochondrial ribosomes by partnering with the mitochondrial methyltransferase NSUN4 and by this means it regulates mitochondrial protein translation [22]. Global loss of MTERF4-NSUN4 complexes leads to embryonic lethality, whereas heart-specific deletion of either protein leads to reduced assembly of mitochondrial ribosomes and impaired cardiac mitochondrial function that results in premature death [22,23]. Still, the functional relevance of MTERF4 in other tissues, such as BAT, where mitochondria are highly abundant, remains to be explored.