Rf-2 Gene Modulates Proteinuria and Albuminuria Independently of Changes in Glomerular Permeability in the Fawn-Hooded Hypertensive Rat

Rangel-Filho, Artur; Sharma, Mukut; Datta, Yvonne H.; Moreno, Carol; Roman, Richard J.; Iwamoto, Yoshiki; Provoost, Abraham P.; Lazar, Jozef; Jacob, Howard J.

doi:10.1681/asn.2005010029

Cited by 58 publications

(64 citation statements)

References 36 publications

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“…198,202 Moreover, an identified missense variant in Cubilin (CBN) has been associated with albuminuria in the general population and in patients with diabetes. 203 In the genetic mapping studies in inbred rat models only a few molecular variants have been clearly identified to date, including Arp3 in the BUF rat 19 and Rab38 in the FHH rat 104,105 (Table 3), although no variant has been ultimately confirmed, for example, by single gene congenic strains or further transgenic models. Nevertheless, given their phenotypic characteristics the panel of rat models summarized here represents an important tool in our armamentarium to explore the genetics of the most prevalent forms of complex CKD to which both arterial hypertension and type-2 diabetes mellitus are major contributors.…”

Section: Discussionmentioning

confidence: 99%

“…A letter code for each cross or strain combination (specified in Legend Table 4.2) and corresponding references were listed below each QTL entry interesting study by Rangel-Filho et al reported a protein null mutation (G-A) in the translation initiation start codon of Rab38 in FHH (Table 3). 104,105 The exchange of Rf-2 including Rab38 and seven other genes led to the restoration of Rab38 protein expression and a significant reduction of increased albuminuria and proteinuria in congenic FHH.BN-Rab38 compared with FHH (Table 3). 104 In FHH, Rab38 may modulate the tubular processing of filtered proteins without affecting the glomerular filtration barrier leading to proteinuria.…”

Section: Loc501853mentioning

confidence: 99%

“…104,105 The exchange of Rf-2 including Rab38 and seven other genes led to the restoration of Rab38 protein expression and a significant reduction of increased albuminuria and proteinuria in congenic FHH.BN-Rab38 compared with FHH (Table 3). 104 In FHH, Rab38 may modulate the tubular processing of filtered proteins without affecting the glomerular filtration barrier leading to proteinuria. 104 …”

Section: Loc501853mentioning

confidence: 99%

“…103 The genetic basis of albuminuria linked to the Rf-2 on RNO1 was elucidated by identifying Rab38 (RAB38, member RAS oncogene family) as a potential candidate gene within this locus. 104 An Table 4.1 Distribution of QTL associated with renal (disease) phenotypes in the rat genome. A letter code for each cross or strain combination (specified in Legend Table 4.2) and corresponding references were listed below each QTL entry interesting study by Rangel-Filho et al reported a protein null mutation (G-A) in the translation initiation start codon of Rab38 in FHH (Table 3).…”

Section: Loc501853mentioning

confidence: 99%

“…104 In FHH, Rab38 may modulate the tubular processing of filtered proteins without affecting the glomerular filtration barrier leading to proteinuria. 104 …”

Section: Loc501853mentioning

confidence: 99%

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Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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During the last two decades, significant progress in our understanding of the development of kidney diseases has been achieved by unravelling the mechanisms underlying rare familial forms of human kidney diseases. Due to the genetic heterogeneity in human populations and the complex multifactorial pathogenesis of the disease phenotypes, the dissection of the genetic basis of common chronic kidney diseases (CKD) remains a difficult task. In this regard, several inbred rat models provide valuable complementary tools to uncover the genetic basis of complex renal disease phenotypes that are related to common forms of CKD. In this review, data obtained in nine experimental rat models, including the Buffalo (BUF), Dahl salt-sensitive (SS), Fawn-hooded hypertensive (FHH), Goto-Kakizaki (GK), Lyon hypertensive (LH), Munich Wistar Frömter (MWF), Sabra hypertension-prone (SBH), spontaneously hypertensive rat (SHR) and stroke-prone spontaneously hypertensive rat (SHRSP) inbred strains, that contributed to the genetic dissection of renal disease phenotypes are presented. In this panel of inbred strains, a large number of quantitative trait loci (QTL) linked to albuminuria/proteinuria and other functional or structural kidney abnormalities could be identified by QTL mapping analysis and follow-up studies including consomic and congenic rat lines. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is suitable for making a significant contribution to the development of an integrated approach to the systems genetics of common CKD. INTRODUCTIONCommon forms of chronic kidney diseases (CKD) represent complex disease phenotypes that are influenced by both environmental and genetic factors. [1][2][3][4][5] Both arterial hypertension and type-2 diabetes mellitus are major contributors to complex CKD, which has a high prevalence in the general human population worldwide affecting B11-15% of individuals in Europe and United States. 6-9 CKD represents as expected a major risk factor for the progression to end-stage renal disease but associates also with an increased risk of cardiovascular morbidity and mortality. 10,11 In addition to the assessment of impaired renal function or glomerular filtration rate, urinary albumin excretion rate (albuminuria) represents another important clinical marker for the evaluation of CKD and cardiovascular risk of patients. [10][11][12][13][14][15] These renal disease phenotypes are also inherited in several inbred rat strains many of which are hypertensive. 16 During the last decades, genetic mapping studies by genome-wide linkage analysis followed by fine mapping of selected quantitative trait loci (QTL) for renal disease phenotypes were reported. Subsequently, studies in consomic and congenic rats were performed to further unravel the genetics of kidney injury in inbred rat strains. For QTL confirmation, consomic strains were generated by transfer of an entire chromosome carrying a QTL from a donor strain into the disease backgro...

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Section: Discussionmentioning

confidence: 99%

Section: Loc501853mentioning

confidence: 99%

Section: Loc501853mentioning

confidence: 99%

Section: Loc501853mentioning

confidence: 99%

“…104 In FHH, Rab38 may modulate the tubular processing of filtered proteins without affecting the glomerular filtration barrier leading to proteinuria. 104 …”

Section: Loc501853mentioning

confidence: 99%

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