title: Rab38 modulates proteinuria in model of hypertension-associated renal disease.
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.
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Rangel-Filho
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.forename: Aron
authors.initials: A
authors.lastname: Geurts
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology; D055786:Gene Knockout Techniques; D006200:Hair Color / Q000235:genetics; D006977:Hypertension, Renal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology; D018374:LLC-PK1 Cells; D016253:Microscopy, Immunoelectron; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D055647:Rats, Transgenic; D013552:Swine; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C498787:Rab38 protein, rat; D020691:rab GTP-Binding Proteins