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Full Review Molecular Disease Presentation in Diabetic Nephropathy Nephrol Dial Transplant (2015) 30: iv17–iv25 doi: 10.1093/ndt/gfv267 Full Review Molecular disease presentation in diabetic nephropathy Downloaded from https://academic.oup.com/ndt/article/30/suppl_4/iv17/2324968 by guest on 25 September 2021 Andreas Heinzel1, Irmgard Mühlberger1, Gil Stelzer2, Doron Lancet2, Rainer Oberbauer3, Maria Martin4 and Paul Perco1 1emergentec biodevelopment GmbH, Vienna, Austria, 2Weizmann Institute of Science, Rehovot, Israel, 3Medical University of Vienna, Vienna, Austria and 4EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, UK Correspondence and offprint requests to: Paul Perco; E-mail: [email protected] ABSTRACT INTRODUCTION Diabetic nephropathy, as the most prevalent chronic disease of Kidney disease is a common problem in patients with diabetes. the kidney, has also become the primary cause of end-stage Depending on the degree of GFR impairment and/or albumin- renal disease with the incidence of kidney disease in type 2 dia- uria, roughly 30% of subjects are affected. As with most betics continuously rising. As with most chronic diseases, the diabetes-associated comorbidities, the pathophysiology is pathophysiology is multifactorial with a number of deregulated multifactorial and the molecular pathways involved in the ini- molecular processes contributing to disease manifestation and tiation and progression constitute a wide and complex as well as progression. Current therapy mainly involves interfering in the redundant network of regulators. Considerable success has renin–angiotensin–aldosterone system using angiotensin-con- been achieved in uncovering certain aspects of molecular regu- verting enzyme inhibitors or angiotensin-receptor blockers. lation of these processes. The most prominent examples are the Better understanding of molecular processes deregulated in identification of the causal contribution of the renin–angioten- the early stages and progression of disease hold the key for de- sin–aldosterone system (RAAS) as well as the matrix metallo- velopment of novel therapeutics addressing this complex dis- proteinase network (MMP) [1, 2]. However, this gain in ease. With the advent of high-throughput omics technologies, knowledge did not lead to an equal success in the discovery researchers set out to systematically study the disease on a mo- of actual drugs that could prevent or slow down the pace of fi lecular level. Results of the rst omics studies were mainly fo- this progressive disease. The only exception is the invention cused on reporting the highest deregulated molecules between of the blockade of the RAAS at several different sites by using diseased and healthy subjects with recent attempts to integrate angiotensin-converting enzyme (ACE) inhibitors or angioten- fi ndings of multiple studies on the level of molecular pathways sin-receptor blockers (ARBs) [3–5]. and processes. In this review, we will outline key omics studies There are several valid explanations for this uncomfortable on the genome, transcriptome, proteome and metabolome level situation but probably the most striking cause lies in the multi- in the context of DN. We will also provide concepts on how to factorial and highly redundant nature of the molecular pathways fi integrate ndings of these individual studies (i) on the level of of this disease. The revolutions in information technology as well functional processes using the gene-ontology vocabulary, (ii) as the omics technologies, however, offer nowadays new oppor- on the level of molecular pathways and (iii) on the level of tunities to uncover these complex molecular signal cascades thus – phenotype molecular models constructed based on protein laying the ground for potentially uncovering diagnostic and protein interaction data. prognostic as well as therapeutic leads to tackle this highly preva- Keywords: biological pathways, diabetic nephropathy, lent clinical problem. This review highlights the most recent re- functional annotation, molecular disease modeling, omics search in this area and provides rational strategies of how to profiling proceed in the fight against diabetic nephropathy (DN). If at © The Author 2015. Published by Oxford University Press iv17 on behalf of ERA-EDTA. All rights reserved. least some of these in-silico concepts of rational marker and drug understanding of the role of hyperglycaemia in the early pro- design will prove successful in clinical trials then a major step for- gression of glomerulosclerosis, a significant drawback was the ward will have been made towards an improved care of patients lack of annotation for more than a half of the identified mole- with diabetes. Needless to say, such concepts have the potential cules at that time. to be applied to other multifactorial entities and are by no means A few years later, the first oligonucleotide arrays were avail- limited to DN. In this manuscript, we will specifically outline key able to study transcriptional changes with an increased cover- omics studies conducted in the area of DN as well as analyse con- age of the full transcriptome, and new players as, for example, cepts on a functional level, on the level of molecular pathways members of the Wnt signalling pathway, were identified as and on the level of biological networks being applied to get a dee- contributors to the pathophysiology of DN [17]. per understanding of the pathophysiology of DN. A recurring conclusion in published DN transcriptomics studies is the importance of oxidative stress underlying fibrosis OMICS studies in diabetic nephropathy for DN progression. Morrison et al. [18] found an up-regulation of several thiol antioxidative genes in rat mesangial cells treated A number of omics studies have been conducted in the past Downloaded from https://academic.oup.com/ndt/article/30/suppl_4/iv17/2324968 by guest on 25 September 2021 couple of years with a focus on DN, as also indicated by the with high glucose concentrations, and Cheng et al. [19] identified MEDLINE query ‘diabetic nephropathies[majr] AND (gene increased concentrations of members of the thioredoxin system expression profiling[mh] OR microarray analysis OR proteo- under comparable experimental conditions in mice. mics[mh] OR metabolomics[mh] OR genome-wide associ- While in-vitro and animal studies mainly concentrated on the ation study[mh]) NOT review’ resulting in 151 publications. glomeruli, transcriptomics studies of microdissected human kid- Representative studies with a focus on disease pathophysiology ney biopsies from DN patients showed relevant changes in for each omics category were selected for this review, also com- gene-expression profiles also in the tubulointerstitial compart- plemented by the authors’ personal paper collections as well as ment, including several nuclear factor-kappaB targets as well as selected references of key articles. Supplementary Data, Table 1 genes linked to inflammation [20, 21] and angiogenesis [17]. holds the discussed omics studies with information on biologic- Comparisons of compartment-specific gene-expression changes al processes presented in the respective Results and Discussion identified common deregulated mechanisms in glomeruli and sections. The reader is also referred to the succeeding articles tubuli associated with cell proliferation [22] and Janus kinase within this special issue dedicated to the individual omics tracks signalling [23], pointing towards the role of hypertrophy and for an extended discussion of performed studies. fibrosis in DN. Meanwhile, transcriptomics studies on DN are no longer Genomics studies in DN. A significant number of Genome- confined to the protein-coding regions of the genome. Argryo- Wide Association Studies (GWAS) in the context of DN has poulos et al. [24] used miRNA arrays and could identify urinary concentrated on patients of African ancestry [6, 7], who have miRNA profiles that differ across the different stages of DN. a disproportionately high risk for developing type II diabetes Proteomics studies in DN. FULL REVIEW mellitus [8]. Single-nucleotide polymorphisms in the MHY9 The majority of proteomics stud- gene are known to be highly associated with ESRD in this popu- ies in DN focus on the identification of biomarker panels. In lation [9, 10] and could also be linked to DN [6, 7]. More recently, particular, studies in the urine of DN patients resulted in a it was shown that MHY9 variants also mediate DN susceptibility number of potential markers showing altered concentration in European Americans [11]. Other SNPs discussed in the con- when compared with healthy controls like, e.g. the ribosomal text of DN are located in the FRMD3 gene [6, 12], and results ubiquitin fusion protein UBA52 [25] or alpha 1 antitrypsin, from GWAS based on samples from the multi-ethnic Family the latter also showing an up-regulation in diseased kidney Investigation of Nephropathy and Diabetes (FIND) study in- biopsies in areas of renal fibrosis [26]. clude SNPs near the genes CNDP1 [13], CACNB2, ARL5 and Jin et al. [27] reported on a diagnostic panel of three potential NEBL [14]. markers, namely alpha-1-antitrypsin, alpha-1-acid glycoprotein In search of genetic determinants explaining the lower inci- 1 and prostate stem cell antigen. Zuerbig et al. [29] showed that denceofDNindiabeticwomen,aGWASintheFinnish the previously identified prognostic classifier for chronic kidney Diabetic Nephropathy (FinnDiane) cohort identified variants disease consisting of 273 urinary peptides (CKD273) [28]was in a region between the two transcription factors SP3 (which capable of predicting development
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