Mechanism of the nephrogenic repair response. Studies on proliferation and vimentin expression after 35S-1,2-dichlorovinyl-L-cysteine nephrotoxicity in vivo and in cultured proximal tubule epithelial cells.
Studies were performed in vivo using 35S-(1,2-dichlorovinyl)-L-cysteine, a nephrotoxin that damages the S3 segment of the proximal tubule after metabolism to a reactive intermediate. Initiation of damage (35S covalent binding) was complete by 6 hour, and an early proliferative response was observed by 24 hour in the S2 or S3C segments. Necrosis in the S3M and increased blood urea nitrogen were maximal at 48 hours and were accompanied by an increase in proliferation of cells at the wound site. Regeneration was marked by the appearance of vimentin expressing cells that lacked brush border enzymes. The loss of differentiated character in the regenerative epithelium persisted after the proliferation (bromodeoxyuridine incorporation) had stopped; redifferentiation occurred between days 5 and 13. Much of the process was reproduced by culturing rat kidney proximal tubule epithelial cells in defined medium. As growth increased, the cells expressed vimentin and lost brush border marker enzymes. However, as the cells reached high density and stopped dividing there was an increase in brush border markers, as was seen in vivo. Vimentin expression did not decrease, however. The data support a mechanism for damage and nephrogenic repair composed of 1) interaction of the toxin with the target cells, 2) necrosis and exfoliation, 3) loss of differentiation and cell growth, 4) recovery of the damaged area and cessation of cell growth, and 5) differentiation of the quiescent cells. Nephrogenic repair may have similarities with the differentiation of the tubular epithelium during development.
Wallin
A
A
W. Alton Jones Cell Science Center, Lake Placid, New York.
Zhang
G
G
Jones
T W
TW
Jaken
S
S
Stevens
J L
JL
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D007633:Keratins / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000473:pathology; D008954:Models, Biological; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains; D014508:Urea / Q000097:blood; D014746:Vimentin / Q000096:biosynthesis* / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis
D014746:Vimentin; C039961:S-(1,2-dichlorovinyl)cysteine; D007633:Keratins; D014508:Urea; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D003545:Cysteine