Abstract
We previously reported that the fawn-hooded hypertensive (FHH) rat is a natural Rab38 knockout, supported by a congenic animal (FHH.BN-Rab38) having less proteinuria than FHH animals. Because these congenic animals contain BrownNorway (BN) alleles for five other named genes; however, a causal role for Rab38 in the FHH phenotype remains uncertain. Here, we used transgenic and knockout models to validate Rab38 and to exclude other genes within the 1.5 Mb congenic region from involvement in causing the FHH phenotype. Transgenic rats homozygous for the wild-type Rab38 BN allele on the FHH background exhibited phenotypic rescue, having 43% lower proteinuria and 75% lower albuminuria than nontransgenic FHH littermates. Conversely, knockout of the Rab38 gene on the FHH.BN-Rab38 congenic line recapitulated a proteinuric phenotype indistinguishable from the FHH strain. In addition, in cultured proximal tubule LLC-PK1 cells, knockdown of Rab38 mRNA significantly decreased endocytosis of colloidal gold-coupled albumin, supporting the hypothesis that Rab38 modulates proteinuria through effects on tubular re-uptake and not by altering glomerular permeability. Taken together, these findings validate Rab38 as a gene having a causal role indeterminingthe phenotype of the FHHrat, whichmodels hypertension-associated renal disease. Furthermore, our data suggest that Rab38 affects urinary protein excretion via effects in the proximal tubule.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 283-292 |
| Number of pages | 10 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 24 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 31 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Nephrology
Cite this
Rab38 modulates proteinuria in model of hypertension-associated renal disease. / Rangel-Filho, Artur; Lazar, Jozef; Moreno, Carol; Geurts, Aron; Jacob, Howard J.
In: Journal of the American Society of Nephrology, Vol. 24, No. 2, 31.01.2013, p. 283-292.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rab38 modulates proteinuria in model of hypertension-associated renal disease
AU - Rangel-Filho, Artur
AU - Lazar, Jozef
AU - Moreno, Carol
AU - Geurts, Aron
AU - Jacob, Howard J.
PY - 2013/1/31
Y1 - 2013/1/31
N2 - We previously reported that the fawn-hooded hypertensive (FHH) rat is a natural Rab38 knockout, supported by a congenic animal (FHH.BN-Rab38) having less proteinuria than FHH animals. Because these congenic animals contain BrownNorway (BN) alleles for five other named genes; however, a causal role for Rab38 in the FHH phenotype remains uncertain. Here, we used transgenic and knockout models to validate Rab38 and to exclude other genes within the 1.5 Mb congenic region from involvement in causing the FHH phenotype. Transgenic rats homozygous for the wild-type Rab38 BN allele on the FHH background exhibited phenotypic rescue, having 43% lower proteinuria and 75% lower albuminuria than nontransgenic FHH littermates. Conversely, knockout of the Rab38 gene on the FHH.BN-Rab38 congenic line recapitulated a proteinuric phenotype indistinguishable from the FHH strain. In addition, in cultured proximal tubule LLC-PK1 cells, knockdown of Rab38 mRNA significantly decreased endocytosis of colloidal gold-coupled albumin, supporting the hypothesis that Rab38 modulates proteinuria through effects on tubular re-uptake and not by altering glomerular permeability. Taken together, these findings validate Rab38 as a gene having a causal role indeterminingthe phenotype of the FHHrat, whichmodels hypertension-associated renal disease. Furthermore, our data suggest that Rab38 affects urinary protein excretion via effects in the proximal tubule.
AB - We previously reported that the fawn-hooded hypertensive (FHH) rat is a natural Rab38 knockout, supported by a congenic animal (FHH.BN-Rab38) having less proteinuria than FHH animals. Because these congenic animals contain BrownNorway (BN) alleles for five other named genes; however, a causal role for Rab38 in the FHH phenotype remains uncertain. Here, we used transgenic and knockout models to validate Rab38 and to exclude other genes within the 1.5 Mb congenic region from involvement in causing the FHH phenotype. Transgenic rats homozygous for the wild-type Rab38 BN allele on the FHH background exhibited phenotypic rescue, having 43% lower proteinuria and 75% lower albuminuria than nontransgenic FHH littermates. Conversely, knockout of the Rab38 gene on the FHH.BN-Rab38 congenic line recapitulated a proteinuric phenotype indistinguishable from the FHH strain. In addition, in cultured proximal tubule LLC-PK1 cells, knockdown of Rab38 mRNA significantly decreased endocytosis of colloidal gold-coupled albumin, supporting the hypothesis that Rab38 modulates proteinuria through effects on tubular re-uptake and not by altering glomerular permeability. Taken together, these findings validate Rab38 as a gene having a causal role indeterminingthe phenotype of the FHHrat, whichmodels hypertension-associated renal disease. Furthermore, our data suggest that Rab38 affects urinary protein excretion via effects in the proximal tubule.
UR - http://www.scopus.com/inward/record.url?scp=84873357210&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873357210&partnerID=8YFLogxK
U2 - 10.1681/ASN.2012090927
DO - 10.1681/ASN.2012090927
M3 - Article
C2 - 23291471
AN - SCOPUS:84873357210
VL - 24
SP - 283
EP - 292
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 2
ER -