ADAM19 expression in human nephrogenesis and renal disease: associations with clinical and structural deterioration.
ADAM19, an enzyme from the ADAM (a disintegrin and metalloproteinase) family, is involved in various cell-cell and cell-matrix interactions. It can cleave epidermal growth factor (EGF)-like growth factors, such as heparin-binding (HB)-EGF and neuregulin (NRG), from the cell membrane. ADAM-mediated EGF receptor activation is crucial in the development of renal pathology. Based on these data, we studied ADAM19 in human nephrogenesis and renal disease. We collected 20 fetal kidneys and 56 biopsies from patients with various renal diseases. The unaffected part of kidneys from eight patients with renal cell carcinoma served as control. RNA in situ hybridization revealed widespread ADAM19 mRNA expression in the nephrogenic zone of human fetal kidneys. Normal human kidneys showed constitutive ADAM19 expression in distal tubules and endothelial cells, whereas proximal tubules were negative. In renal disease, ADAM19 was de novo expressed in proximal tubules and glomerular mesangium and upregulated in distal tubules and endothelial cells. ADAM19 colocalized with tubular and interstitial NRG, however, not with HB-EGF. Independent of renal disorder, mesangial ADAM19 expression was associated with glomerular damage as assessed by mesangial matrix expansion, focal glomerulosclerosis, and glomerular macrophage influx (all P<0.001). ADAM19 in proximal tubules and in peritubular capillaries was associated with interstitial fibrosis (P<0.05). Finally, increasing tubular ADAM19 was associated with declining renal function (P<0.05). The abundant ADAM19 expression during nephrogenesis points to a role in growth promotion and regulation. The high ADAM19 expression in renal disease suggests involvement in profibrotic and proinflammatory processes leading to renal deterioration.
Melenhorst
W B W H
WB
Department of Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. w.b.w.h.melenhorst@path.umcg.nl
van den Heuvel
M C
MC
Timmer
A
A
Huitema
S
S
Bulthuis
M
M
Timens
W
W
van Goor
H
H
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002648:Child; D003627:Data Interpretation, Statistical; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005865:Gestational Age; D005920:Glomerular Mesangium / Q000166:cytology; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000473:pathology; D006084:Graft Rejection; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016030:Kidney Transplantation; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D066246:ErbB Receptors; D051722:ADAM Proteins; C411902:ADAM19 protein, human