Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.
Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.
Wharram
Bryan L
BL
University of Michigan Health System, Division of Nephrology, Department of Internal Medicine, 1570 MSRBII, Box 0676, Ann Arbor, MI 48109-0676, USA.
Goyal
Meera
M
Wiggins
Jocelyn E
JE
Sanden
Silja K
SK
Hussain
Sabiha
S
Filipiak
Wanda E
WE
Saunders
Thomas L
TL
Dysko
Robert C
RC
Kohno
Kenji
K
Holzman
Lawrence B
LB
Wiggins
Roger C
RC
D000818:Animals; D002452:Cell Count; D004167:Diphtheria Toxin / Q000494:pharmacology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D050199:Podocytes / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes
D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface