Diagnosis of Alport syndrome—search for proteomic biomarkers in body fluids

Pohl, Michael; Danz, Karin; Groß, Oliver; John, U; Urban, Johannes; Patzer, Ludwig; Habbig, Sandra; Feldkötter, Markus; Witzke, Oliver; Walther, Mario; Rhode, Heidrun

doi:10.1007/s00467-013-2533-5

Cited by 15 publications

(13 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The development of early biomarkers is currently a priority in the Alport field, as it may provide a sensitive means of monitoring response of emergent therapies (27). It would thus be useful to determine whether urinary ET-1 levels are elevated in pre-proteinuric Alport patients.…”

Section: Discussionmentioning

confidence: 99%

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

Dufek

Meehan

Delimont

et al. 2016

Kidney International

View full text Add to dashboard Cite

Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the sub-capillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of pro-inflammatory cytokines and metalloproteinases. These events drive the progression of glomerulonephritis. Here we test whether endothelial cell-derived endothelin-1 is upregulated in Alport glomeruli, and further elevated by hypertension. Treatment of cultured mesangial cells with endothelin-1 activates the formation of drebrin-positive actin microspikes. These microspikes do not form when cells are treated with the endothelin A receptor antagonist sitaxentan, or under conditions of siRNA knockdown of endothelin A receptor mRNA. Treatment of Alport mice with sitaxentan results in delayed onset of proteinuria, normalized glomerular basement membrane morphology, inhibition of mesangial filopodial invasion of the glomerular capillaries, normalization of glomerular expression of metalloproteinases and pro-inflammatory cytokines, increased lifespan, and prevention of glomerulosclerosis and interstitial fibrosis. Thus endothelin A receptor activation on mesangial cells is a key event in initiation of Alport glomerular disease in this model.

show abstract

Section: Discussionmentioning

confidence: 99%

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

Dufek

Meehan

Delimont

et al. 2016

Kidney International

View full text Add to dashboard Cite

show abstract

“…Despite the long‐lasting application of APPs as common but nonspecific diagnostic and prognostic parameters, some distinct sets of APPs have recently been proposed as specific biomarkers, particularly with proteomic and glycoproteomic searches in body fluids. This has also been reflected in our studies with respect to a broad range of diseases like sepsis or acute respiratory infection , congenital or acquired nephropathies , and psoriasis . Unfortunately, many of these results were neglected by the scientific community and considered as not being of value of the low specificity of acute phase reactants in many diseases, sometimes by the discoverers themselves.…”

Section: Introductionmentioning

confidence: 86%

Acute phase proteins as promising biomarkers: Perspectives and limitations for human and veterinary medicine

Schrödl

Büchler

Wendler

et al. 2016

Proteomics Clinical Apps

Self Cite

View full text Add to dashboard Cite

Acute phase proteins (APPs) are highly conserved plasma proteins that are increasingly secreted by the liver in response to a variety of injuries, independently of their location and cause. APPs favor the systemic regulation of defense, coagulation, proteolysis, and tissue repair. Various APPs have been applied as general diagnostic parameters for a long time. Through proteomic techniques, more and more APPs have been discovered to be differentially altered. Since they are not consistently explainable by a stereotypic hepatic expression of sets of APPs, most of these results have unfortunately been neglected or attributed to the nonspecificity of the acute phase reaction. Moreover, it appears that various extrahepatic tissues are also able to express APPs. These extrahepatic APPs show focally specific roles in tissue homeostasis and repair and are released primarily into interstitial and distal fluids. Since these focal proteins might leak into the circulatory system, mixtures of hepatic and extrahepatic APP species can be expected in blood. Hence, a selective alteration of parts of APPs might be expected. There are several hints on multiple molecular forms and fragments of tissue-derived APPs. These differences offer the chance for multiple selective determinations. Thus, specific proteoforms might indeed serve as tissue-specific disease indicators.

show abstract

“…The use of next-generation sequencing or whole-exome sequencing in the initial evaluation of monosymptomatic and oligosymptomatic glomerular hematuria, prior to tissue biopsy, may become more widespread as access to these methods spreads and costs decrease, as is already occurring in the United Kingdom and Europe. Identification of sensitive and specific biomarkers for Alport syndrome could contribute to targeted application of genetic analysis 56, 57 .…”

Section: Evolving Changes In Diagnostic Evaluationmentioning

confidence: 99%

Alport syndrome: facts and opinions

Kashtan

2017

F1000Res

View full text Add to dashboard Cite

show abstract

Diagnosis of Alport syndrome—search for proteomic biomarkers in body fluids

Abstract: These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.

Cited by 15 publications

References 27 publications

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

Acute phase proteins as promising biomarkers: Perspectives and limitations for human and veterinary medicine

Alport syndrome: facts and opinions

Contact Info

Product

Resources

About