Holthofer, Harry

Huber, Tobias B.

Cell and Tissue Research

English

Helsingin yliopiston digitaalinen arkisto

EDITORIALFrom genetics to personalized nephrology: kidney researchat a tipping pointTobias B. Huber1,2,3,4 & Harry Holthofer4,5Published online: 2 June 2017# Springer-Verlag Berlin Heidelberg 2017Keywords Kidney . Genetics . Podocytes . Ciliopathy .Disease modelingIntroductionTechnologies for genetic analysis continue their evolution atan amazing pace, including advances in whole genome se-quencing, total RNA sequencing and single cell genomics.Complementary to these, total sequencing and analytical ser-vices are increasingly becoming commercial with rapid andhigh quality service provision. These developments have ledto the full availability of genetic analysis to ever wider re-search communities and consequent advances in a variety ofresearch areas, while the fundamentals have not changed: withall of the novel tools that are becoming available, criticalthinking and alertness shown by well-trained cliniciansworking seamlessly together with scientists remain the keyto success.The technical advances are, furthermore, changing the val-ue of discovery research and the way that it integrates into thefurther development of solutions for direct patient benefit: thebiopharmaceutical and diagnostic industries need to co-operate with the best producers of discovery data, which usu-ally come from universities and research institutions. Thesedevelopments also call for increasing adherence to qualitystandards in genetics, patient data and massive sample repos-itories with repercussions in legal and commercial issues. Wecan fairly state that, in many ways, the traditional researchconcepts are at crossroads and must re-adjust. The researchcommunity working on kidney diseases has been early toadapt and, consequently, has benefitted hugely from the newtechnologies and approaches.In this special issue of Cell and Tissue Research, calledBGenetic Kidney Diseases^, we present the leading edge ofresearch achievements, novel approaches and prospects forthe future so that we can better anticipate the next level ofresearch into hereditary and acquired kidney diseases.Genetics of kidney diseasesGenetic kidney diseases account for a considerable fraction ofend stage renal kidney disease. Novel monogenetic causes,genetic modifiers and new risk gene variants for kidney dis-eases have been discovered at an amazing pace in recent years.This knowledge is currently being translated into a muchdeeper understanding of the pathophysiology of many renaldiseases.In his article BNew structural insights into podocyte biolo-gy ,̂ Florian Grahammer (2017) highlights the latest advancesin light- and electron-microscopic techniques and shows theirskilful application in revealing the remaining controversies in* Tobias B. Hubert.huber@uke.de* Harry Holthoferharry.holthofer@helsinki.fi1 Department of Medicine IV, Faculty of Medicine, MedicalCenter-University of Freiburg, Freiburg, Germany2 III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf,Hamburg, Germany3 BIOSS Centre for Biological Signalling Studies and Center forBiological Systems Analysis (ZBSA), Albert-Ludwigs University,Freiburg, Germany4 Freiburg Institute for Advanced Studies, Albert-Ludwigs UniversityFreiburg, Freiburg, Germany5 Institute for Molecular Medicine Finland (FIMM), University ofHelsinki, Helsinki, FinlandCell Tissue Res (2017) 369:1–4DOI 10.1007/s00441-017-2637-5the assembly of key elements composing the glomerular filtra-tion barrier. Notably, the novel imaging approaches have led to anew understanding of the way that the congenital nephrosisgene product NEPHRIN together with NEPH1 forms the slitdiaphragm, an advance that will hopefully translate into a betterunderstanding of proteinuric diseases.In his article BRole of primary cilia in non-dividing andpost-mitotic cells^, Gerd Walz (2017) describes yet anotherintriguing aspect, namely the role of primary cilia in differen-tiated post-mitotic cells in the regulation of, for example,DNA damage responses, autophagy and mitochondrial func-tions. By integrating these different cellular functions, primarycilia in non-dividing cells seem to form a signalling hub con-trolling cell homeostasis.Apoptosis is a known regulatory process in the develop-ment of the polycystic diseases in the kidney. In their articleBRole of apoptosis in the development of polycystic kidneydiseases^, Peintner and Borner (2017) summarize key factorsaffecting the balance in the polycystin-1- and polycystin-2–based multiprotein membrane complex and its consequencesfor regulating cell survival, proliferation, differentiation andautophagy in polycystic kidney disease.The article BInsights into autosomal dominant polycystickidney disease by quantitative mass spectrometry-basedproteomics^ by Diedrich and Dengjel (2017) shows the powerof advanced mass-specrometry (MS) methods in revealing thecomplex of proteins and their respective associations withintracellular structures and pathways in autosomal polycystickidney disease. More generally, their review shows that theleading edge technical approach to protein analytics can be ofimmense help in understanding disease pathogenesis, proteinmodifications and protein-protein interactions in general.Notably, the prospect of MS-based technologies for diseasediagnostics and monitoring is discussed, paving the way fortheir future use as a support in clinical disease management.Fabry disease is a lysosomal storage disease with oftendevastating kidney manifestations. In their articleBPathomechanisms of renal Fabry disease^, Eikrem et al.(2017) summarize the genetic background and pathophysio-logic details of this glycosphingolipid disorder. Of note, nextto the enzyme replacement therapy that is used as clinicalroutine, novel chaperone-mediated therapies have recently en-tered the clinical arena. Therefore, Fabry disease represents aBmodel disease^ of the way that genetic and pathophysiologicdiscovery are providing novel clinical treatment strategies.Skin and kidney share not only some basic structural mo-lecular components but also distinct overlapping diseases. Intheir review article BRenal-skin syndromes^, Has and He(2017) provide a comprehensive overview highlighting thispreviously underrecognized disease group. Diseases sharedby the skin and the kidney are related to defects in cell-matrix adhesion and the key molecular players at the sharedsites and experimental models are introduced by these authors.Furthermore, distinct types of epidermolysis bullosa arereviewed in depth with a description of their respective renalinvolvement.Mechanisms, consequences and the regulation of the epi-genetic machinery have rapidly been unfolded, with an in-creasing understanding of the way that DNA methylationand histone modifications affect disease progression. In theirarticle BEpigenetics of kidney disease^, Wanner and Bechtel-Walz (2017) summarize current knowledge of the renal cellepigenome in development, maintenance and kidney diseasethereby offering a novel basis for comprehending renal dis-ease initiation and progression. Furthermore, the promise ofepigenetics for biomarker discovery and emerging new treat-ments are discussed.In his article BAdvances in renal genetic diagnosis^,Bergmann (2017) highlights the benefits that recent technicaladvances of next-generation sequencing (NGS) has providedin disease diagnosis and the identification of the pathophysi-ology of hereditary nephropathies. The increasing knowledgeof the genotype-phenotype correlation not only provides thebasis for genetic counselling, risk assessment and clinicalmanagement but also offers new therapeutic concepts for sev-eral genetic diseases.Disease modeling in genetic kidney diseasesThe advances in identifying causal gene mutations or genevariants associated with kidney diseases offer new opportuni-ties for basic research and the development of therapeuticcompounds. In recent years, scientists have been creatingmodels of human genetic disease by using organoids, worms,flies, zebrafish, frogs, mice and other animals to gain novelinsights into the molecular mechanisms of many renaldiseases.In their article BGenetic kidney diseases: Caenorhabditiselegans as model system^, Ganner and Neumann-Haefelin(2017) review the possibilities of fully utilizing the simplenematode for studies of disease and developmental aspectsof the kidney. The abundance of genetic similarities betweenhuman species and C. elegans allows the study of slit dia-phragm biology, ciliopathies, tubulogenesis and generalmechanisms of cellular homeostasis.Helmstädter and Simons (2017) review the experimentaluses, advantages and limitations of Drosophila in studyinghuman kidney disease in BUsing Drosophila nephrocytes ingenetic kidney disease^. The high conservation of humanpodocyte and proximal tubular cell functions by Drosophilanephrocytes make them a highly valuable kidney model asevidenced by recent work. Because of the easy genetic acces-sibility of Drosophila, this model can be a game changer infuture studies aimed at distinguishing disease-causing se-quence variants from functional gene variants present in thehuman genome.2 Cell Tissue Res (2017) 369:1–4Schenk et al. (2017) review the recent advances inzebrafish models with regard to studying kidney diseases inBDisease modeling in genetic kidney diseases: zebrafish^. Themajor benefits of using zebrafish are the relative simplicity ininducing genetic manipulations and in monitoring renal func-tions, even in real time. Recently developed high-throughputscreening and genome editing techniques offer tremendousopportunities to model kidney diseases in zebrafish.Getwan and Lienkamp (2017) discuss the implications ofthe Xenopus tadpole: BToolbox in a tadpole: Xenopus for kid-ney research^. With the obvious benefits of the rapid embry-onic development of Xenopus and the availability of targetedinjections, the tadpole offers obvious benefits for studying, inparticular, organogenesis and genetic diseases. In this article,the authors review the variety of methods employed so far andthose coming increasingly into use, including those for geneediting. As the authors point out in the article, the use of thetadpole system has provided instrumental insight into the mo-lecular mechanisms of human kidney disease.For decades, mice with engineered genomes have beenmost extensively used for targeted studies of kidney patho-physiology and genetics. In their article BDisease modelingin genetic kidney diseases: mice^, Andreas F. Hofmeisterand colleagues (2017) now provide a comprehensive surveyto the methods currently in use and the results obtained for abetter understanding of the biology of the respective disease-causing genes.Ganna Reint and coworkers (2017) in their article BKidneydevelopment and perspectives for organ engineering^ provideintriguing views of alternative developments for future kidneyreplacement. In particular, they highlight the emerging tech-niques of using decellurized and three-dimensionalbioprinting strategies.In their article BEngineering the kidney: novel approachestowards reprogramming and directed differentiation of renalcells^, Kaminski et al. (2017) review the most recently devel-oped techniques for generating renal cells and tissues by eitherdirected differentiation or transcription-factor-basedreprogramming. These novel tools offer exciting possibilitiesfor modeling inherited and acquired kidney diseases frompatient-derived cells, for performing nephrotoxicity testing,or for potentially developing novel kidney replacementtherapies.New aspects of cell metabolism, soluble factors,biomarkers and cell quantification in kidney diseaseIn recent years, the cell metabolism of renal cells, the solublefactors mediating glomerular diseases, the previously under-appreciated cell compartments such as parietal epithelial cellsand novel biomarkers have all entered the center stage ofkidney disease discovery research.As has been known for a long time, metabolic signaling andenergy metabolism play a critical role in genetic and acquiredkidney disease. In their article BMetabolism and homeostasis inthe kidney: metabolic regulation through insulin signaling in thekidney ,̂ Kuczkowski and Brinkkoetter (2017) show that thekidney is not just a passive target of systemic metabolic changesbut that renal cell intrinsic metabolic signaling pathways aremain drivers of renal disease. With the emphasis on insulinsignaling, the authors provide a comprehensive review of thecurrent understanding and the link between insulin signalingandmitochondrial function contributing importantly to the path-ogenesis of kidney disease.The kidney is either an active participant or an innocentbystander suffering from collateral damage of immunologicalactions. The manner in which the kidney interacts in molecu-lar terms with other tissues and cross talks with the immuno-logical system has seen substantial advances in recent years,especially in the form of circulating factors tentatively identi-fied in the pathogenesis of idiopathic nephrotic syndrome. Intheir review article BExtrarenal determinants of kidney filterfunction^, Hahm et al. (2017) provide comprehensive insightinto the derivation of suPAR (from the bone-marrow), its reg-ulation and its promise not only as a target, but also as apotential high-value diagnostic biomarker for the managementof this devastating kidney disease.These ubiquitous vehicles of cell-to-cell communicationand other fundamental biological functions are reviewed byBarreiro and Holthofer (2017) in their article BUrinary extra-cellular vesicles. A promising shortcut to novel biomarkerdiscoveries^. Whereas the re-discovery of these vesicles ofvarious size categories and overlapping physico-chemicalproperties is highlighted by results indicating their value inchanging our understanding of many of the biological path-ways involved, the lack of standardization results in partiallymisleading and overenthusiastic interpretations. Nevertheless,extracellular vesicles are increasingly relevant for kidney re-search because of the new and efficient methods of harvestingthem from urine.Loss of podocytes appears to be the pacemakers of mostprogressive kidney diseases. In their article BQuantifyingpodocyte depletion: theoretical and practical considerations^,Victor Puelles and colleagues (2017) provide valuable insightsinto podocyte depletion in disease pathogenesis by introduc-ing currently available methods for quantifying podocyte de-pletion. These methods include, for example, the analysis oftheir number from glomerular cross-sections, stereologicalmethods and new techniques allowing glomerular analysis inoptically cleared samples. The review provides a balancedevaluation in all of these techniques suitable for podocytequantitation and will be of practical help in the selection ofmethods for use.Whereas glomerular visceral epithelial cells (podocytes)have long been considered as cornerstones in manyCell Tissue Res (2017) 369:1–4 3proteinuric kidney diseases, the role of glomerular parietalepithelial cells (PECs) of the Bowman’s capsule has remainedenigmatic and controversial. In their review article BParietalcells-new perspectives in glomerular disease^, Laura Miesenand coworkers (2017) provide a comprehensive new under-standing of this cell type. By reviewing the evidence regardingtheir important roles as a reservoire for the replacement of lostpodocytes and as the site of extracapillary proliferative lesionsin glomerular disease, their true pathogenetic role becomesevident. We expect to see future aspects of their role revealedby the use of targeted experimental models and more accuratetechniques of imaging. Future developments of targeted ther-apeutics aimed at PECs can also be expected.We feel that the leading edge researchers with their veryhigh quality contributions in this special issue provide an ex-cellent observation point enabling us to see the direction fromwhich the field has come and the route along which kidneyresearch and drug development is now heading.We warmly thank all the contributors for sharing their time,commitment and special expertise in research-intensive ne-phrology with our readers. The outcome of this special issuespeaks for itself and we hope that this special issue paves theway to future discoveries for the benefit of our kidneypatients.ReferencesBarreiro K, Holthofer H (2017) Urinary extracellular vesicles. A promis-ing shortcut to novel biomarker discoveries. Cell Tissue Res. doi:10.1007/s00441-017-2621-0BergmannC (2017) Advances in renal genetic diagnosis. Cell Tissue Res.doi:10.1007/s00441-017-2636-6Diedrich B, Dengjel J (2017) Insights into autosomal dominant polycystickidney disease by quantitative mass spectrometry-based proteomics.Cell Tissue Res. doi:10.1007/s00441-017-2617-9Eikrem Ø, Skrunes R, Tøndel C, Leh S, Houge G, Svarstad E, Marti HP(2017) Pathomechanisms of renal Fabry disease. Cell Tissue Res.doi:10.1007/s00441-017-2609-9Ganner A, Neumann-Haefelin E (2017) Genetic kidney diseases:Caenorhabditis elegans as model system. Cell Tissue Res doi:10.1007/s00441-017-2622-zGetwan M, Lienkamp SS (2017) Toolbox in a tadpole: Xenopus forkidney research. Cell Tissue Res. doi:10.1007/s00441-017-2611-2Grahammer F (2017) New structural insights into podocyte biology. CellTissue Res. doi:10.1007/s00441-017-2590-3Hahm E, Peev V, Reiser J (2017) Extrarenal determinants of kidney filterfunction. Cell Tissue Res. doi:10.1007/s00441-017-2635-7Has C, He Y (2017) Renal-skin syndromes. Cell Tissue Res. doi:10.1007/s00441-017-2623-yHelmstädter M, Simons M (2017) Using Drosophila nephrocytes in ge-netic kidney disease. Cell Tissue Res. doi:10.1007/s00441-017-2606-zHofmeister AF, Kömhoff M, Weber S, Grgic I (2017) Disease modelingin genetic kidney diseases: mice. Cell Tissue Res. doi:10.1007/s00441-017-2639-3Kaminski MM, Tosic J, Pichler R, Arnold SJ, Lienkamp SS (2017)Engineering kidney cells: reprogramming and directed differentia-tion to renal tissues. Cell Tissue Res. doi:10.1007/s00441-017-2629-5Kuczkowski A, Brinkkoetter PT (2017) Metabolism and homeostasis inthe kidney: metabolic regulation through insulin signaling in thekidney. Cell Tissue Res. doi:10.1007/s00441-017-2619-7Miesen L, Steenbergen E, Smeets B (2017) Parietal cells—new perspec-tives in glomerular disease. Cell Tissue Res. doi:10.1007/s00441-017-2600-5Peintner L, Borner C (2017) Role of apoptosis in the development ofautosomal dominant polycystic kidney disease (ADPKD). CellTissue Res. doi:10.1007/s00441-017-2628-6Puelles VG, Bertram JF, Moeller MJ (2017) Quantifying podocyte deple-tion: theoretical and practical considerations. Cell Tissue Res. doi:10.1007/s00441-017-2630-zReint G, Rak-Raszewska A, Vainio SJ (2017) Kidney development andperspectives for organ engineering. Cell Tissue Res. doi:10.1007/s00441-017-2616-xSchenkH,Müller-Deile J, Kinast M, SchifferM (2017)Disease modelingin genetic kidney diseases: zebrafish. Cell Tissue Res. doi:10.1007/s00441-017-2593-0Walz G (2017) Role of primary cilia in non-dividing and post-mitoticcells. Cell Tissue Res. doi:10.1007/s00441-017-2599-7Wanner N, Bechtel-Walz W (2017) Epigenetics of kidney disease. CellTissue Res. doi:10.1007/s00441-017-2588-x4 Cell Tissue Res (2017) 369:1–4

From genetics to personalized nephrology : kidney research at a tipping point

Tobias B. Huber

Harry Holthofer

Crossref

From genetics to personalized nephrology: kidney research at a tipping point

Holthöfer, Harry

FreiDok plus

https://helda.helsinki.fi/bitstream/10138/237088/1/10.1007_s00441_017_2637_5.pdf

From genetics to personalized nephrology : kidney research at a tipping point

Abstract

Similar works

Full text

Available Versions

Helsingin yliopiston digitaalinen arkisto

Crossref

FreiDok plus