Rab38 modulates proteinuria in model of hypertension-associated renal disease

Artur Rangel-Filho, Jozef Lazar, Carol Moreno, Aron Geurts, Howard J. Jacob

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)283-292
Number of pages10
JournalJournal of the American Society of Nephrology
Volume24
Issue number2
DOIs
StatePublished - Jan 31 2013
Externally publishedYes

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Renal Hypertension
Proteinuria
Congenic Animals
Phenotype
Alleles
LLC-PK1 Cells
Genes
Transgenic Rats
Gold Colloid
Gene Knockout Techniques
Albuminuria
Endocytosis
Albumins
Permeability
Messenger RNA
Proteins

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 journalArticle

Rangel-Filho, Artur ; Lazar, Jozef ; Moreno, Carol ; Geurts, Aron ; Jacob, Howard J. / Rab38 modulates proteinuria in model of hypertension-associated renal disease. In: Journal of the American Society of Nephrology. 2013 ; Vol. 24, No. 2. pp. 283-292.
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