Acute kidney injury (AKI) was classified using the Kidney Disease: Publisher: La incidencia de la lesión renal aguda en la población. La injuria renal aguda (IRA) es una condición común, sobre todo en pacientes therapies for the treatment of critically ill patients with acute kidney injury (AKI). Acute renal failure (ARF) is an independent risk factor associated with increased mortality during sepsis. Recent consensus definitions have allowed the.
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Novel biomarkers of Acute Kidney Injury. We are also grateful to F. They have become the most critical biological mediators characterized in the last ten years. Increasing evidence demonstrates that microRNAs are key regulators of the normal kidney function and development, but they are also at the basis of several renal diseases. Recent works have established that these molecules can be secreted to extracellular environments, enabling their detection in peripheral body fluids such as urine and serum.
Moreover, circulating miRNAs detected in body fluids turn into suitable biomarkers of kidney diseases, including acute kidney injury. This new generation of renal biomarkers could have a great impact in the clinical practice, significantly contributing to improve patient management. In this review, we discuss over the implication of microRNAs in normal kidney function and homeostasis as well as the role of circulating miRNAs as novel biomarkers of kidney diseases, focusing on their potential usefulness in acute kidney injury management.
Moreover, their deregulation is frequently associated with disease development. More than miRNAs have been described in the human genome, 2 a number comparable to the known leskon of transcription factors or other regulatory proteins. Moreover miRNAs show very specific expression patterns among tissues and cell types. Their akl of action is based on recognition of small sequences in their target mRNAs.
This dynamic regulation has unveiled them as key regulators of a wide range of cellular events, including rapid responses to stress. A new cleavage produces a double stranded RNA molecule of 22 nucleotides.
Strand selection mechanism has not been completely elucidated yet. This complex, joined to other controlling factors, is ayuda for driving mRNA degradation or translation repression, as will be further detailed in following sections.
Nucleotides in positionscalled seed sequence, are essential for pairing with the target mRNA and miRNA function. This mechanism is principally found in plants but is very agudx in mammals. When pairing with target sequences is partially complementary, which is the most frequent mechanism in mammals, miRNA regulation is produced by mRNA translation repression or degradation. However this degradation process is different and involves recruitment of deadenylase complexes that remove or shorten the poly-A tail of the target transcript.
Schematic representation of miRNA transcription, maturation and function by translational repression or mRNA cleavage. Although the contribution rate of mRNA decay and translational repression to miRNA action is a controversial topic, it seems clear that target degradation provides a major contribution to silencing in mammal cells.
Half-lives of some miRNAs could reach many hours or even days in some organs like the liver or the heart. Indeed, some miRNAs expressed in the retina and involved in darkness adaptation present a half-life of approximately 1 hour.
These interesting data point out that more attention needs to be focused on miRNA turnover as miRNA lesiob regulation could emerge as a potential critical step in miRNA function. Due to the relevance of miRNA function and implication in a wide range of processes such as organ development, homeostasis and pathophysiology, miRNA studies in kidney development and function have emerged as a field of intense research during the last few years.
Several profiling studies have revealed microRNA profiles related to specific organs, including the kidney. In fact, lack of miRNA activity causes defects in kidney terminal differentiation such as decreased proliferation rate, aberrant zki patterning and delayed terminal differentiation of kidney tubules.
In this regard, miR and miR family strictly regulate the temporal and spatial expression pattern of transcription factors involved in pro-nephron maturation. Loss of microRNAs in nephron progenitors leads to early depletion of this cell population as renal growth progresses. These effects are especially due to the regulation by miRa, miRb and miRp of Bim, a pro-apoptotic factor which increases its expression levels when miRNAs are depleted. On reanl other hand, some microRNAs have been related to kidney senescence.
Particularly, overexpression of miR and miRa in mesangial cells leads to premature senescence of ernal cell population by the regulation of mitochondrial antioxidative enzymes.
Studies based on DICER knockdown in podocytes, juxtaglomerular cells and proximal tubules have unveiled the role of miRNAs in kidney function maintenance as well as specific miRNA roles in each kidney compartment. KO of DICER in glomerulus results in progressive loss of podocyte function leading to proteinuria and kidney function impairment and ultimately leading to animal death.
DICER deletion in juxtaglomerular cells produces acute loss of this cell type leading to an abrupt decrease of renin expression in kidney and deregulation of blood pressure. Several microRNAs have also been unveiled as critical regulators of kidney function and homeostasis maintenance. For instance, miRa is a direct regulator of Aquoporin 1 and 4, which are integral membrane transporters involved in water homeostasis. All these studies indicate that miRNAs play critical roles in normal renal function and physiology maintenance and when altered, may lead to renal diseases.
Specific miRNAs deregulation has been linked to renal disease development. Lesioj example, miR has been identified as a critical regulator of collagen production in diabetic nephropathy. This downregulation is directly correlated with tubulointerstitial fibrosis and low glomerular filtration rate GFR in diabetic patients.
Reduction of this microRNA increases the expression of Cdc25A, a regulator of cell leesion, promoting cyst growth.
On the other hand, the miR family are repressors of E-cadherin during epithelial to mesenchimal transition EMTpromoting cell migration and invasion during metastasis.
Biomarkers in acute kidney injury: Evidence or paradigm?
Intravenous injection of microvesicles confers functional and morphologic protection of renal cells by enhancing tubular cell proliferation and reducing apoptosis and leukocyte infiltration. These miRNAs also protect kidney from chronic damage progression by inhibiting glomerulosclerosis and tubulointerstitial fibrosis.
Even though the initial studies proposed that miRNAs were only present inside the cell, it has been demonstrated that they can also be secreted to the extracellular environment with potential functional consequences. On the other hand, as mentioned before, miRNA deregulation has been associated with the development of a wide range of pathologies. Due to these features, physiological or pathological regulation of intracellular miRNAs may also modify the panel of secreted miRNAs.
Indeed, changes in serum miRNAs profiles have been unveiled as useful markers of a wide range of diseases including cancer, cardiovascular disease, stroke and nephropathies as well as physiological states such as pregnancy. Moreover, serum miRNAs have demonstrated great stability and resistance to aggressive conditions such as RNAse treatment, or drastic pH changes. Taken together, all these features demonstrate that serum circulating miRNAs achieve nearly all the required characteristics for an ideal biomarker.
Their presence in a peripheral fluid allows diagnosis by minimum invasive methods and samples can be easily and routinely obtained in clinical practice. In addition to their high stability in fresh samples, several studies have demonstrated that miRNAs maintain stability and reliability in long-term stored serum samples and in samples conserved at room temperature for hours.
These characteristics, joined to their tissue and cell type specificity, have revealed circulating miRNAs as promising biomarkers for more accurate diagnosis and monitoring of diseases. Regarding the advantage of circulating miRNAs as precise biomarkers in comparison to the ones available up to now, it is important to notice that miRNAs could belong to the pathophysiological mechanisms responsible for diseases, including renal diseases.
Therefore, miRNAs could provide the clinician with critical additional information that is currently not accessible and they could also be considered as novel therapeutic targets.
Despite the intense research in the circulating miRNAs field of the last years, publications about their role as AKI biomarkers are still scarce. However, during the last two years some articles have started to point out this issue.
Los microARN en el riñón: nuevos biomarcadores de la lesión renal aguda
Lorenzen JM et al. Bioinformatics analysis of the target genes of these microRNAs evidenced that they were enriched in pathways related to apoptosis and cell proliferation. A recent publication by Lan YF et al. Moreover, detection of this miRNA in leesion showed that miR expression is 60 fold higher in AKI patients compared to healthy controls.
All these studies demonstrated that miRNAs could be precise biomarkers of AKI diagnosis useful in clinical practice, offering valuable additional information in comparison with classical biomarkers. The information provided here identifies miRNAs as very promising molecules for increasing the knowledge of pathophysiological mechanisms underlying kidney diseases and very powerful tools for improving clinical management of renal patients.
Although it was not the main topic of this review, miRNAs could also be considered as novel therapeutic targets in renal diseases. Identification of microRNAs as novel biomarkers for AKI could drastically change current clinical practice allowing earlier detection and better patient monitoring and handling. Thus they could identify patients at risk, allow an early diagnosis and an accurate monitoring of the syndrome. They could also be predictive biomarkers of patient outcome, with important consequences in the clinical practice.
Phase 3 Specific Biomarkers are able to monitor injury and repair. In this regard, serum miRNA levels correlate with severity and different recovery degrees. In summary, miRNAs have started to emerge as key players in many relevant diseases, including nephropathies. This review has aimed to introduce and overview miRNAs as exciting molecules in Experimental Nephrology and promising tools in Clinical Nephrology.
The authors declare that they have no conflicts of interest related to the contents of this article. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet ;11 9: Kozomara A, Griffiths-Jones S. Nucleic Acids Res ;39 Database issue: Regulation of microRNA biogenesis and function. Thromb Haemost ; 4: Huntzinger E, Izaurralde E. Gene silencing by microRNAs: Nat Rev Genet ;12 2: Control of stress-dependent cardiac growth and gene expression by a microRNA.
INSUFICIENCIA RENAL AGUDA ASOCIADA CON SEPSIS
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