Medical College of Wisconsin
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Rab38 modulates proteinuria in model of hypertension-associated renal disease. J Am Soc Nephrol 2013 Feb;24(2):283-92

Date

01/08/2013

Pubmed ID

23291471

Pubmed Central ID

PMC3559491

DOI

10.1681/ASN.2012090927

Scopus ID

2-s2.0-84873357210 (requires institutional sign-in at Scopus site)   38 Citations

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 Brown Norway (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 in determining the phenotype of the FHH rat, which models hypertension-associated renal disease. Furthermore, our data suggest that Rab38 affects urinary protein excretion via effects in the proximal tubule.

Author List

Rangel-Filho A, Lazar J, Moreno C, Geurts A, Jacob HJ

Author

Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Disease Models, Animal
Endocytosis
Gene Knockout Techniques
Hair Color
Hypertension, Renal
Kidney
Kidney Tubules, Proximal
LLC-PK1 Cells
Microscopy, Immunoelectron
Proteinuria
RNA, Small Interfering
Rats
Rats, Inbred BN
Rats, Transgenic
Swine
rab GTP-Binding Proteins