ESPN 54th Annual Meeting

ESPN 2022


 
Transcriptomic and proteomic profiles of chronic kidney disease in pediatric arteriolar tissues: which pathways are involved in pro-calcifying processes?
JULIE BERNARDOR 1 MARIA BARTOSOVA 1 CONGHUI ZHAN 1 IVA MARINOVIC 1 BETTI SCHAEFER 1 REBECCA HERZOG 2 ANETTE MELK 3 GUENTER KLAUS 4 KLAUS ARBEITER 5 RIMANTE CERKAUSKIENE 6 DOROTA DROZDZ 7 DELPHINE FARLAY 8 ARIANEB MEHRABI 9 JUN_ OH_ 10 KLAUS KRATOCHWILL 2 CLAUS PETER SCHMITT 1

1- DIVISION OF PEDIATRIC NEPHROLOGY, CENTER FOR PEDIATRIC AND ADOLESCENT MEDICINE, UNIVERSITY OF HEIDELBERG, 69120 HEIDELBERG, GERMANY
2- CHRISTIAN DOPPLER LABORATORY FOR MOLECULAR STRESS RESEARCH IN PERITONEAL DIALYSIS, DIVISION OF PEDIATRIC NEPHROLOGY AND GASTROENTEROLOGY, DEPARTMENT OF PEDIATRICS AND ADOLESCENT MEDICINE, COMPREHENSIVE CENTER FOR PEDIATRICS, MEDICAL UNIVERSITY OF VIENNA, VIENNA, AUSTRIA
3- DEPARTMENT OF PEDIATRIC NEPHROLOGY, HEPATOLOGY AND METABOLIC DISEASES, CHILDRENS HOSPITAL, HANNOVER MEDICAL SCHOOL, GERMANY
4- KFH PEDIATRIC KIDNEY CENTER, MARBURG, GERMANY
5- DEPARTMENT OF PEDIATRICS AND ADOLESCENT MEDICINE, MEDICAL UNIVERSITY VIENNA, AUSTRIA
6- PEDIATRIC CENTER, VILNIUS UNIVERSITY, LITHUANIA
7- JAGIELLONIAN UNIVERSITY MEDICAL COLLEGE, KRAKOW, POLAND
8- INSERM UMR S1033 RESEARCH UNIT, LYON, FRANCE
9- DEPARTMENT OF GENERAL, VISCERAL AND TRANSPLANTATION SURGERY, UNIVERSITY HOSPITAL HEIDELBERG, HEIDELBERG, GERMANY
10- DEPARTMENT OF PEDIATRIC NEPHROLOGY, UNIVERSITY CHILDRENS MEDICAL CLINIC, UNIVERSITY MEDICAL CENTER HAMBURG-EPPENDORF, GERMANY
 
Introduction:

 Pediatric patients with chronic kidney disease (CKD) develop major atherosclerosis and vascular calcification until early adulthood; underlying mechanisms are partially understood only. Early mechanisms of vascular calcification in children with CKD devoid of aging and life-style related damage should be particularly sensitive and should allow identification of novel therapeutic targets.

Material and methods:

 Gene set enrichment and Ingenuity pathway analysis were performed on multi-omics data sets obtained from micro-dissected omental arterioles from children with normal renal function and with CKD5 (n=7/group; age 7.3 ± 3/6.8 ± 3 years). Based on extensive literature review, we established a vascular calcification pathway library comprising 442 biological processes/molecular functions and extracted linked genes from Gene Ontology database. Histomorphometry was performed in 90 non-CKD and 100 CKD5 children, pathways identified by omics were validated in independent patient cohorts (n=30). Calcium deposits were assessed by Von Kossa staining and electronic microscopy.

Results:

 Arteriolar lumen to vessel ratio was significantly reduced in CKD5 vs. age matched controls (0.75 (IQR 0.1) vs. 0.56 (0.1), p<0.001). Von Kossa staining yielded significant arteriolar calcification in CKD5, currently characterized by electron microscopy. Vascular calcification pathway analyses identified 21/442 pathways significantly regulated on arteriolar transcriptome (p<0.05; FDR=0.25) level related to complement activation, Wnt signaling, extracellular matrix organization, endoplasmic reticulum stress, apoptosis, autophagy and ossification. 9/442 calcification related arteriolar proteome pathways were enriched and included complement activation, extracellular matrix organization, fatty acid metabolism (all p<0.0001), calcium ion binding (p<0.005), apoptosis (p<0.05); Fibronectin-1 is a key hub-gene. In independent age-matched cohorts, CKD5 children had shorter endothelial telomeres and less endothelial methylated histone 3. Endothelial complement system was activated, C1q and terminal complement complex deposition increased.

Conclusions:

 Vascular calcifications are already present in young children with CKD5. Arteriolar multi-omics analyses and independent protein validation identified specific molecular pathomechanisms; of which several represent potential therapeutic targets.