Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

Bilušić, Marijo; Bataillard, Alain; Tschannen, Michael; Gao, Li; Barreto, Nadia E.; Vincent, Madeleine; Wang, Tao; Jacob, Howard J.; Sassard, J; Kwitek, Anne E.

doi:10.1161/01.hyp.0000144542.57306.5e

Cited by 50 publications

(62 citation statements)

References 33 publications

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“…16,122,123 Strain characteristics LH rats demonstrate mild spontaneous, salt-sensitive hypertension, proteinuria and albuminuria and exhibit several features common to the human metabolic syndrome including dyslipidemia, insulin resistance and glucose intolerance. [124][125][126][127] Cosegregation and linkage analyses Two linkage analyses were performed by using a male LH Â LN F2 population for BP, anthropometry, renal, metabolic and endocrine phenotypes. 124,126 For the renal phenotype, data QTL were demonstrated for creatinine levels on RNO1, RNO2 and RNO17 and for kidney weight phenotypes on RNO1-RNO3, RNO10 and RNO17, while no linkage for proteinuria, albuminuria or structural kidney damages was reported (Table 1).…”

Section: Lyon Hypertensive Rat Strain Breedingmentioning

confidence: 99%

“…[124][125][126][127] Cosegregation and linkage analyses Two linkage analyses were performed by using a male LH Â LN F2 population for BP, anthropometry, renal, metabolic and endocrine phenotypes. 124,126 For the renal phenotype, data QTL were demonstrated for creatinine levels on RNO1, RNO2 and RNO17 and for kidney weight phenotypes on RNO1-RNO3, RNO10 and RNO17, while no linkage for proteinuria, albuminuria or structural kidney damages was reported (Table 1). 126 In addition, several QTLs linked to BP could be detected on RNO2, RNO13 and RNO17.…”

Section: Lyon Hypertensive Rat Strain Breedingmentioning

confidence: 99%

“…124,126 For the renal phenotype, data QTL were demonstrated for creatinine levels on RNO1, RNO2 and RNO17 and for kidney weight phenotypes on RNO1-RNO3, RNO10 and RNO17, while no linkage for proteinuria, albuminuria or structural kidney damages was reported (Table 1). 126 In addition, several QTLs linked to BP could be detected on RNO2, RNO13 and RNO17. 126 …”

Section: Lyon Hypertensive Rat Strain Breedingmentioning

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: Lyon Hypertensive Rat Strain Breedingmentioning

confidence: 99%

Section: Lyon Hypertensive Rat Strain Breedingmentioning

confidence: 99%

Section: Lyon Hypertensive Rat Strain Breedingmentioning

confidence: 99%

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Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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“…4 Overlapping quantitative trait loci were later found for blood pressure in a cross between Dahl salt-sensitive and Brown Norway rats 5 and for kidney mass (a blood pressure-related trait) in a cross between Lyon hypertensive and Lyon normotensive rats. 6 Moreover, linkage between premature hypertension and a region on chromosome 2 was shown in a human family in Kyrgyzstan. 7 This region is, in part, orthologous to the rat chromosome 3.…”

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confidence: 99%

“…For the in vitro data Student´s T test or Mann-Whitney U test was applied depending on the distribution of the data. p-values (2-sided) were considered significant at p<0.05. , and Bilusic et al 6 and have been named BP177, BP152, and KIDM13, respectively, according to the Rat Genome Database (www.rgd.mcw.edu). The proximal region of rat chromosome 3 is in part orthologous to human chromosome 2q (indicated in grey), while the distal region is homologous to human chromosome p11.…”

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Knockdown of the Hypertension-Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish ( Danio rerio )

Kirsch

Kaufeld²,

Korstanje³

et al. 2013

Hypertension

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Abstract-Hypertension is one of the major risk factors for chronic kidney disease. Using quantitative trait loci analysis, we identified the gene of the F-BAR protein NOSTRIN in the center of an overlapping region in rat and human quantitative trait loci that are associated with hypertension. Immunohistochemical analysis revealed a predominantly podocytic expression pattern of NOSTRIN in human and mouse glomeruli. Further, NOSTRIN colocalizes with cell-cell contactassociated proteins β-catenin and zonula occludens-1 and interacts with the slit-membrane-associated adaptor protein CD2AP. In zebrafish larvae, knockdown of nostrin alters the glomerular filtration barrier function, inducing proteinuria and leading to ultrastructural morphological changes on the endothelial and epithelial side and of the glomerular basement membrane of the glomerular capillary loop. We conclude that NOSTRIN expression is an important factor for the integrity of the glomerular filtration barrier. Disease-related alteration of NOSTRIN expression may not only affect the vascular endothelium and, therefore, contribute to endothelial cell dysfunction but might also contribute to the development of podocyte disease and proteinuria. Results NOSTRIN Is Expressed in Glomerular PodocytesImmunostainings with a polyclonal antibody directed against a peptide localized near the C terminus of rodent NOSTRIN revealed that NOSTRIN is expressed in peritubular capillaries and glomerular structures ( Figure 1A). Double stainings with podocytic and endothelial markers showed that glomerular NOSTRIN expression could be assigned to podocytic structures ( Figure 1B). A strong colocalization of NOSTRIN and the endothelial cell marker thrombomodulin could be observed in vascular structures outside the glomerulus (data not shown). Immunostainings of human kidney sections with an antibody directed against human NOSTRIN confirmed podocytic distribution pattern in the glomerulus ( Figure 1C). NOSTRIN Interacts With Cell Contact-Associated Proteins in Human PodocytesTo further characterize NOSTRIN expression in podocytes, we performed double stainings of NOSTRIN with the cell contact-associated proteins β-catenin and zonula occludens-1 in cultured human podocytes. As depicted in Figure 2A, NOSTRIN displayed a close colocalization with β-catenin and zonula occludens-1 in regions of cell-cell contacts ( Figure 2A). Coimmunoprecipitation experiments demonstrated that NOSTRIN interacts with cell-cell contact-specific proteins β-catenin, CD2AP, and caveolin-1 ( Figure 2B). Knockdown of NOSTRIN Induces a Renal Phenotype in ZebrafishTo prove that NOSTRIN is relevant for the integrity of the glomerular filtration barrier, we analyzed functional effects of NOSTRIN loss on the kidney in vivo in larval zebrafish. Although rat or human NOSTRIN is only 44% homologous to their zebrafish equivalent, the different functional domains remain conserved between the different species indicating that the zebrafish NOSTRIN orthologue might have similar functions ( Figure 3A). After inj...

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