RGD Reference Report - Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. - Rat Genome Database

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Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.

Authors: Wharram, BL  Goyal, M  Wiggins, JE  Sanden, SK  Hussain, S  Filipiak, WE  Saunders, TL  Dysko, RC  Kohno, K  Holzman, LB  Wiggins, RC 
Citation: Wharram BL, etal., J Am Soc Nephrol 2005 Oct;16(10):2941-52. Epub 2005 Aug 17.
RGD ID: 1556472
Pubmed: PMID:16107576   (View Abstract at PubMed)
DOI: DOI:10.1681/ASN.2005010055   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344-Tg(NPHS2-HBEGF)WigRatglomerulosclerosis inducedIMPdiphtheria toxin RGD 
HBEGFHumanglomerulosclerosis inducedIDA  RGD 
HbegfRatglomerulosclerosis inducedISOHBEGF (Homo sapiens) RGD 
HbegfMouseglomerulosclerosis inducedISOHBEGF (Homo sapiens) RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344-Tg(NPHS2-HBEGF)WigRatdecreased podocyte number inducedIMPdiphtheria toxin RGD 
F344-Tg(NPHS2-HBEGF)WigRatincreased urine protein level inducedIMPdiphtheria toxin RGD 
Objects Annotated

Genes (Rattus norvegicus)
Hbegf  (heparin-binding EGF-like growth factor)

Genes (Mus musculus)
Hbegf  (heparin-binding EGF-like growth factor)

Genes (Homo sapiens)
HBEGF  (heparin binding EGF like growth factor)

Strains
F344-Tg(NPHS2-HBEGF)Wig  (NA)


Additional Information