Abstract
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.
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Introduction
Common 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 ∼11–15% of individuals in Europe and United States.6, 7, 8, 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 background of a recipient strain or vice versa.17 For QTL fine mapping analysis, congenic or subcongenic strains were established by transfer of chromosomal fragments of different length from the donor to the recipient background or vice versa.16, 17
The aim of this report is to review the current status of genetic mapping studies of genetic determinants of kidney damage in these inbred rat models.
Buffalo rat
Strain breeding
The proteinuria-prone Buffalo/Mna (BUF) inbred rat strain was derived from random bred BUF rats, and established at Nagoya University in Japan.18, 19 This inbred strain demonstrated spontaneous thymomas.19, 20, 21
Strain characteristics
The normotensive22 BUF rat strain develops spontaneous progressive proteinuria23, 24, 25 in the nephrotic range, that is, >150 mg per 24 h,26 hypoproteinemia,23 abnormal lipid metabolism,23 structural renal lesions such as focal and segmental glomerulosclerosis (FSGS) and glomerular epithelial cell alterations with foot process effacement later in life.22, 23, 25, 27, 28, 29 Both proteinuria and FSGS are not linked to the genetic susceptibility to develop spontaneous thymomas21, 25, 27, 30, 31 and related immune disorder phenotypes.32, 33 Furthermore, BUF rats show muscle atrophy, fatigability and weakness.34, 35
Cosegregation and linkage analyses
Linkage analysis in a male (BUF × Wistar Kyoto (WKY)/NCrj) F1 × BUF backcross population revealed significant linkage only to one locus, that is, the QTL Pur1 (Proteinuria QTL 1) on rat chromosome (RNO)13 linked to the development of proteinuria (Tables 1 and 5).24 Interestingly, this QTL explained about 39% of the total variance of proteinuria in the backcross population.24 Further, fine mapping of Pur1 by linkage analysis, physical mapping and single-nucleotide polymorphism analysis narrowed the QTL to a 7.8-Mb long region containing 38 genes of which 25 remained potential candidate genes for proteinuria.19 Subsequently, in Arp3 (actin-related protein 3) a missense mutation (L111F substitution) was found causing actin assembly abnormalities in podocytes (Table 3).19 This mutation was related to both proteinuria and FSGS development in the BUF rat.19 No consomic or congenic studies were reported.
Dahl rat
Strain breeding
Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rat strains were originally established as outbred strains from Sprague-Dawley rats by Lewis K Dahl.36 DS and DR rats were selected for contrasting blood pressure (BP) values in response to high dietary salt intake (8% NaCl).16, 37 The inbred Dahl rat strains Dahl salt-sensitive (SS/Jr) and Dahl salt-resistant (SR/Jr) were derived from outbred DS and DR rats by Rapp.16
Strain characteristics
SS/Jr rats are characterized by salt-sensitive hypertension,16, 38 progressive proteinuria in response to high-salt diet and kidney damage, which is associated with glomerular, tubulointerstitial and vascular damage.16, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 Interestingly, SS/Jr develops early onset spontaneous albuminuria at 4 weeks of age already when fed a normal/low-salt diet before ultrastructural glomerular changes53 such as segmental loss of podocyte foot processes43 are observed. However, the progression of hypertension and renal damage is attenuated under normal/low-sodium compared with high-sodium diet in aging rats.16, 38, 43, 48, 53, 54 The magnitude of albuminuria is not only enhanced by high-salt intake but also modified by the composition of dietary protein intake.55, 56 In addition, the rats develop left ventricular hypertrophy and fibrosis,47, 49, 51, 57 hyperlipidemia46, 51 and insulin resistance.58, 59, 60
Cosegregation and linkage analyses
Different studies addressed the genetics of albuminuria in SS rats under either normal/low-salt or high-salt diet. Poyan Mehr analyzed the genetic basis of early onset albuminuria on low-salt (0.2% NaCl) diet in SS rats by genome-wide QTL mapping analysis of albuminuria at 8 weeks of age in a large cohort of 539 (SSFub × spontaneously hypertensive rat (SHR)Fub) F2 progeny.53 Seven suggestive or significant UAE QTLs on RNO2, RNO6, RNO8, RNO9, RNO10, RNO11 and RNO19 accounting together for 34% of the overall variance of albuminuria were identified (Tables 1 and 5).53 It was shown that homozygosity of two albuminuria increasing alleles for at least six QTLs was necessary to generate a considerable increase in UAE in young F2 rats.53
Garrett et al.54 identified in a backcross population of 276 male rats derived from F1(Dahl SS/Jr (S) × SHR/NHsd) × S under low salt (0.3% NaCl) 10 albuminuria and/or proteinuria QTL on RNO1–RNO2, RNO6 (QTL1+QTL2), RNO8–RNO11, RNO13 and RNO19, most of which colocalized with QTL for structural kidney lesion phenotypes (Tables 1 and 5). As expected, most of the S alleles were associated with increased albumin or protein excretion rates, although alleles on RN06 (QTL1) and RNO11 were also linked to decreased albumin excretion rates.54 The albuminuria RNO2-QTL was involved in multiple interactions with albuminuria QTL on other chromosomes.54 Subsequently, the authors confirmed in an independent backcross population fed low salt (0.3% NaCl) all previously identified low-salt albuminuria QTL54 except the RNO6-QTL1 and the QTL on RNO10 (Table 1).61 Thus, taken together six common albuminuria QTLs on RNO2, RNO6, RNO8, RNO9, RNO11 and RNO19 were identified in all three studies, respectively (Tables 1 and 5).
Subsequently, further studies analyzed the genetic influence on renal damage in response to high-salt diet in the SS rat. One study again in a backcross between SS and SHR rats demonstrated that the albuminuria/proteinuria QTL on RNO2, RNO11 and RNO19 that were detected under low-salt exposure were not detectable under high-salt diet (Table 1).61 The authors hypothesized that SHR alleles on RNO11 may mediate preglomerular vasoconstriction and hence, protect against renal damage in response to an increased blood pressure after high salt in backcross animals.61 Four of the albuminuria/proteinuria QTL reported in this study on RNO6, RNO8, RNO9 and RNO19 were also confirmed in a similar cross.48 In the latter study, the effect of high-salt intake (4% NaCl) was analyzed in an F2 cross derived from SS/Rkb × SHR/Rkb and led to the identification of overall six albuminuria/proteinuria QTLs on RNO3, RNO6 (2 QTL), RNO8, RNO9 and RNO19 (Tables 1 and 5).48 Moreover, the authors detected also QTL linked to structural kidney injury phenotypes, for example, renal interstitial fibrosis, tubulointerstitial inflammation and renal microangiopathy on RNO20, RNO3 and RNO5, respectively (Tables 1 and 5).48 Of interest, the SHR allele was associated with a more severe phenotype at the tubulointerstitial inflammation and microangiopathy QTL.48
Moreno et al.62 identified in a female-specific linkage analysis of (SS/JrHsdMcwi × Brown Norway (BN)/SsNHsdMcwi) F2 animals 126 QTL for 96 cardiovascular, renal and other traits in response to graduated NaCl intake. A QTL on RNO2 was found to be associated with proteinuria and focal glomerulosclerosis and a QTL on RNO11 with proteinuria and glomerular injury (Tables 1 and 5).
Consomic/congenic studies
Different consomic and congenic/subcongenic studies between SS and SHR or SS and BN were performed to unravel the genetics of kidney damages in SS rats.
SS and SHR
Wendt et al.49 analyzed the effect of replacement of the albuminuria/proteinuria QTL on SS-RNO19 previously described by Siegel et al.48 Transfer of SHR-RNO19 into SS revealed in consomic SS-19SHR a protective effect of RNO19 on albuminuria and proteinuria in both sexes under both low- and high-salt diet (Table 2).49
In different congenic and subcongenic studies, the phenotypic effects of proteinuria and albuminuria QTL that were originally detected under low- and/or high-salt diet on RNO2, RNO6, RNO8, RNO9, RNO11 and RNO1354, 61 were confirmed by transfer from SHR into the SS strain (Table 2).52, 63, 64 The RNO2-QTL demonstrated a major influence on proteinuria/albuminuria and glomerular, tubular and interstitial phenotypes, and fibrosis without influencing BP.61, 65 Recombinant progeny testing refined this QTL on RNO2 to an interval, which spans 1.5 cM or ∼5.0 Mb containing 64 known and/or predicted genes (Table 3).65 Among these candidates, Sfrp2 (secreted frizzled-related protein 2) and Wnt2b (wingless-type MMTV integration site family, member 2B) represent members of the Wnt/β-catenin signalling pathway and are of interest because they are involved in renal fibrosis. Moreover, Cct3 (chaperonin containing TCP1, subunit 3) as another candidate in this interval seems to affect cytoskeleton integrity (Table 3).65
In a reciprocal approach by transfer of SS-RNO8 or SS-RNO13 into the renal-protective SHR background, no significant changes were observed in the derived congenic strains SHR.S(8) and SHR.S(13) for proteinuria, glomerular, tubular or interstitial injury.52
SS and BN
In a complete chromosome, substitution panel involving SS and BN rat designate as SS(/Mwcwi)-xBN(/SSNHsdMcwi) consomics each BN chromosome was transferred into the SS background, respectively.66 For consomic studies, the animals were fed diets with different salt content, for example, normal (0.4%) or high-salt diets (4% or 8% NaCl) and protein compositions, and were also additionally exposed to hypoxia.55, 67, 68 Collectively, it was demonstrated in male rats that proteinuria and/or albuminuria was significantly attenuated by transfer of RNO1, RNO5-8, RNO11, RNO13, RNO16, RNO18 and RNOY from BN into SS (Table 2).55, 67, 68 Interestingly, in corresponding females introgression of each BN chromosome resulted in a significant reduction of proteinuria and/or albuminuria with the exception of RNO3, RNO15, RNO17 and RNOX (Table 2).55, 68 A sexual dimorphism with higher proteinuria levels in male compared with female SS rats was reported in another study and related to a functional effect of RNOX on proteinuria although this has not been confirmed and documented, for example, by data obtained in consomic strains.67 Structural glomerular injury was significantly influenced by RNO1 in male rats (Table 2).68
In addition, transfer of BN-RNO13 (containing the renin gene) into consomic SS.BN13 ameliorated proteinuria levels, medullary interstitial fibrosis, glomerulosclerosis and tubular necrosis in response to high salt (4% NaCl; Table 2).69
Subsequently, in microarray analysis of kidneys from SS and SS.BN13 sequential changes in gene expression were uncovered for many differentially expressed genes on RNO13 (Table 3).70 The microRNA miR-29b was found to affect different collagens and genes related to the extracellular matrix and thus might have a pivotal role in renal medullary injury of SS rats (Table 3).71 Importantly, consomic and congenic strains derived from RNO13 shared not inevitably the same pathways identified in salt-sensitive hypertension and renal damage of the parental SS strain.72 In further subcongenic breeding experiments, the QTL linked to proteinuria development on RNO13 was narrowed to a 1.9-Mb region, which however also affected BP (Table 3).73
Fawn-hooded rat
Strain breeding
The fawn-hooded rat model was selected from a cross of German-brown and white Lashley rats16 and transferred early in 1970 by Tobach of the American Museum of Natural History as a closed outbred colony to Europe74 and afterwards to Unilever Research Laboratories, Vlaardinger, The Netherlands.16 Until the mid 1980s, hypertensive fawn-hooded rats were inbred and selected for high BP denoted as fawn-hooded hypertensive (FHH) or normotension (FHL, fawn-hooded low blood pressure).75, 76
The August × Copenhagen (ACI, AxC9935) rat model is the established original reference strain for FHH and show resistance to hypertension, proteinuria and renal damage.77, 78
Strain characteristics
The FHH strain is homozygous recessive for three coat color genes: red-eyed dilution (r), nonagouti (a) and hooded (h).79, 80 FHH develops hematuria81 and a platelet storage-pool disease leading to a mild bleeding disorder,74, 82 which is based on a single-gene defect on RNO1 containing the r gene.80 In addition, aging animals develop spontaneously systemic and glomerular hypertension and overt malignant nephrosclerosis with renal lesions such as FSGS,83, 84, 85, 86, 87 podocyte injury84, 86 and progressive proteinuria and albuminuria.77, 81, 88 Moreover, a sexual dimorphism with more aggravated hypertension and proteinuria in males compared with females is observed.89 Overall, FHH have a shortened life expectancy.84
In contrast, FHL rats develop also chronic renal failure but less severe hypertension, only mild proteinuria and FSGS.75
Cosegregation and linkage analyses
Two linkage analyses in an (FHH/EUR × ACI)F1 × FHH backcross under normal conditions and in an (FHH/EUR × ACI/NCrEur) F2 cross subjected to unilateral nephrectomy (Nx) were performed in the FHH rat (Table 1).77, 90 The authors identified in both linkage studies overall five QTLs termed as Rf (renal failure) 1–5 locus, respectively; they are linked to renal damage, that is, proteinuria, albuminuria and/or focal glomerulosclerosis. Rf-1 and Rf-2 that are distinct from each other were mapped on RNO1, Rf-3 on RNO3, Rf-4 on RNO14 and Rf-5 on RNO17 (Tables 1 and 5).77, 90 All Rf loci showed no significant effect on systemic BP, except RNO2.77 An independent QTL on RNO1 (Bpfh-1, blood pressure in fawn-hooded-1) on RNO177 was also significantly linked to albuminuria and proteinuria (Tables 1 and 5).90 Interestingly, in response to Nω-nitro-L-arginine methyl ester (L-NAME) the Rf-1 locus was also linked to functional and structural renal damage in FHL rats ascertained by genotype comparison between FHH and FHL.78
Lopez and associates demonstrated in a third linkage analysis in a female F2 population derived from consomic FHH-1BN/Mcwi and FHH/EurMcwi66 a QTL on RNO1 showing a dominant mode of inheritance for impairment of renal blood flow autoregulation in FHH (Tables 1 and 5).90, 91 This QTL mapped to a 12.8-Mb region inside the Rf-1 region (Table 3).90, 91
Consomic/congenic studies
For QTL confirmation and QTL fine mapping, different consomic and congenic studies were generated between FHH and ACI or FHH and BN or for the genetic characterization of kidney injury in FHH.
FHH and ACI
Several congenic strains were established for QTL fine mapping analysis by transfer of different segments of FHH/EUR-Rf loci into the resistant ACI background (Table 2). Thus, in this experimental setting the occurrence of genetic susceptibility to kidney damage in ACI by transfer of Rf loci from FHH was tested. To enhance renal damage susceptibility, that is, albuminuria/proteinuria and focal glomerulosclerosis, in the resistant ACI background, however, animals were subjected to either unilateral nephrectomy (Nx) or NO inhibition by treatment with L-NAME or a combination of both procedures.92, 93, 94, 95, 96 By using this protocol, different segments of the FHH-Rf-1 region in five subcongenic ACI strains directly aggravated indeed the susceptibility of kidney damage and the autoregulation in congenic rats (Table 2).92, 93, 94, 95, 96 Thus, the Rf-1 locus contains at least one gene that might influence the susceptibility to progressive renal failure in the presence of higher BP values due to NO inhibition or Nx.92
Van Dijk et al.93, 95, 96 demonstrated in a congenic Rf-3 strain a slightly increased susceptibility to renal damage (Table 2), while single Rf-4 and Rf-5 congenics appeared normal in comparison with ACI, respectively.
In double-congenic studies, it was demonstrated that the susceptibility to renal damage in FHH was influenced by different synergistic gene–gene interactions.90 Interestingly, it could be shown that in the FHH rat the Rf-1 locus has marked additive effects on other Rf loci, that is, on Rf-3 and Rf-4 (Table 2),90, 93, 95 while the interaction of Rf-1 with Rf-5 exhibited no significant effect on renal damage.96
To further narrow the Rf-3 locus, two triple-congenic strains (Rf-1+3+4_a and Rf-1+3+4_b) were generated, which include different chromosomal segments of the Rf-1, Rf-3 and Rf-4 loci (Table 2). Subsequently, comparative genomics of the triple-congenic strains refined the Rf-3 region denoted as Rf-3_b to 7.1 Mb and 13 known or predicted genes, which directly influence renal impairment, that is, albuminuria, glomerulosclerosis and mean arterial pressure (Table 3). In the Rf-3_b region, pyrosequencing revealed several genes with non-synonomous amino-acid changes (Table 3).97
For fine mapping of the Rf-4 locus, which spanned originally 61.9 Mb, only a 4.1-Mb segment of this FHH locus was introgressed in a minimal congenic Rf-1a+4_a line of the ACI background (Table 2).98 The authors stated that one non-synonymous, intergenic, intronic or untranslated variant(s) between ACI and FHH in the Rf-4_a segment may cause a loss of Nrf2 (Kelch-like ECH-associated protein 1) transcription factor binding site, which may lead to an increase in glomerular permeability to albumin and glomerulosclerosis without a BP influence in FHH rats (Table 3).98 These findings seem to be of further interest, because the 4.1-Mb interval shows homology to human loci and QTL,99, 100 which were linked to renal function.98
FHH and BN
Mattson et al. followed the reciprocal approach and generated a full panel of consomic strains in which each autosome or sex chromosome of FHH/EurMcwi66 was replaced by the corresponding BN/SSNHsdMcw chromosome. Male and female animals were subjected to NO inhibition by treatment with L-NAME and high-salt intake (8% NaCl) to aggravate renal damage susceptibility, that is, albuminuria/proteinuria and structural kidney damage, in the FHH background. The authors demonstrated that renal disease phenotypes including proteinuria, albuminuria or glomerular injury are influenced by RNO1, RNO14, RNO15, RNO16 or RNO18 (Table 2).101, 102
Further studies using BN as the reference strain for FHH generated new insights into the role of Rf-1. Thus, in the congenic FHH.1BNAR+ strain autoregulation of renal blood flow was normalized and a decrease in the progression of renal disease was observed (Table 2).91, 103 It was suggested that before hypertension occurred an impaired autoregulation in FHH may lead to early onset of renal disease such as glomerulosclerosis and renal interstitial fibrosis.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 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.104
Goto-Kakizaki rat
Strain breeding
In 1973, the Goto-Kakizaki (GK) rat model was selected by inbreeding from a non-diabetic Wistar rat colony in Sendai, Japan.106, 107, 108, 109 GK rats demonstrate glucose intolerance upon oral glucose tolerance tests, and a colony was transferred to Europe in 1989.110
Strain characteristics
The GK rats are not obese and develop in both sexes spontaneously with early onset glucose intolerance and mild hyperglycemia, and thus non-insulin-dependent diabetes mellitus.108, 110, 111, 112, 113, 114 In addition, other phenotype such as salt-sensitive hypertension,115 hypertriglyceridemia, endothelial dysfunction,115 microangiopathy and macroangiopathy were observed in GK.110 Older animals develop significant renal damage including glomerular hypertrophy, thickening of the glomerular basement membrane, proliferation of mesangial cells, glomerulosclerosis, tubulointerstitial fibrosis and inflammatory cell infiltration.113, 116, 117, 118 Moreover, some substrains of GK develop increased proteinuria at 24 months of age,118 which might be affected by hypertension.119 Furthermore, GK rats show early development of neuropathy and retinopathy late in life.110
Cosegregation and linkage analyses
Nobrega et al.114 identified in a genome-wide analysis of a salt fed (1% NaCl) GKFL × BN/Mcwi F2 population four loci on RNO1, RNO4, RNO5 and RNO10 linked to early diabetes phenotypes (Tables 1 and 5). Furthermore, from two proteinuria QTLs identified on RNO5 and RNO7, only the QTL on RNO5 colocalized with a diabetes QTL (Tables 1 and 5). Both proteinuria QTLs were also linked to glomerulosclerosis and tubular sclerosis.114 These data indicate that diabetes and proteinuria development in the GK rat model were affected by different genetic mechanisms.114 Further analysis showed that diabetes in GK rats might be affected by chronic inflammatory processes.120 More recently, renal and circulating Nsa2 (Nop-7-associated 2) levels were elevated in GK rats and associated with the development of diabetic nephropathy in this strain.121
No consomic or congenic studies were reported.
Lyon hypertensive rat
Strain breeding
The Lyon hypertensive (LH) rat strain was established in 1969 by breeding of outbred Sprague-Dawley rats, which were selected for high systolic BP.122 In addition, the control strains Lyon normotensive (LN) and Lyon low blood pressure strain were generated.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 × 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 RNO17.126
Consomic studies
Gilibert et al.127 confirmed in consomic studies using BN as a reference strain in an LH-13BN consomic strain, in which BN/NHsdMcwi-RNO13 was transferred into the LH background, the functional relevance of the RNO13 carrying BP-QTL (Table 2).
Interestingly, the LH-13BN consomic strain exhibits a 50% reduction in proteinuria in LH-13BN compared with LH.127 However, it could be not clarified whether the amelioration in proteinuria depends on the lower BP observed in the congenic strain or whether genetic factors on RNO13 control the proteinuria development.127 In contrast, reciprocal introgression of LH-RNO13 into the BN background is not capable of inducing a proteinuria phenotype in the consomic strain BN-13LH.127
Munich Wistar Frömter rat
Strain breeding
The Munich Wistar Frömter (MWF) rat strain was originally selected over several generations for the presence of an increased number of surface glomeruli and originally established as a colony (MWF/Ztm) in Hannover, Germany.128, 129 The colony MWF/FUB renamed as MWF/Rkb and more recently to MWF/FubRkb was established in 1996 by further inbreeding of rats from the original colony at the Charité – Universitätsmedizin Berlin, Germany.130
Strain characteristics
MWF rats develop mild SS spontaneous hypertension, spontaneous albuminuria of early onset, structural renal abnormalities such as an inherited nephron reduction of 30–50%, glomerulosclerosis, reduced podocyte number, renal interstitial fibrosis and endothelial dysfunction.130, 131, 132, 133, 134, 135, 136, 137, 138, 139 Moreover, a sexual dimorphism leads to a more severe manifestation and progression of albuminuria and subsequent renal failure in males compared with females.130, 133, 140
Cosegregation and linkage analyses
Schulz et al. performed two genome-wide linkage analyses in backcross populations between MWF and a normotensive (Lewis/FUB) and a hypertensive (SHR/FUB) reference strain and identified overall 11 different QTLs on 10 rat chromosomes including RNO1 (QTL1 and QTL2), RNO4, RNO6–RNO9, RNO12, RNO15, RNO17 and RNOX, which accounted for albuminuria development in MWF (Tables 1 and 5).130, 141, 142 In addition, six QTLs on RNO1 (QTL1 and QTL2), RNO6, RNO8, RNO15 and RNO17 were linked to proteinuria, and one QTL was linked to renal interstitial fibrosis on RNO6 (Tables 1 and 5).141, 142 Only the albuminuria QTL on RNO6 was identified in both crosses. Overall, the QTL on RNO6 and the QTL on RNO8, which was only detected in the cross between MWF and SHR, exhibited the strongest linkage and phenotypic effects on albuminuria.141, 142 Furthermore, seven QTLs on RNO1–RNO2, RNO6–RNO7, RNO9, RNO13 and RNOX were linked to the number of superficial or surface glomeruli (Tables 1 and 5), while the total number of nephrons was not analyzed in these QTL-mapping studies.141, 142
Consomic studies
The functional role of both major albuminuria QTLs on RNO6 and RNO8 was confirmed by transfer of either RNO6 or RNO8 from SHR into the MWF background.138, 139, 140 Thus, in both single-consomic strains MWF-6SHR and MWF-8SHR, the progressive albuminuria observed in aging male and female MWF was significantly ameliorated (Table 2).138, 139, 140 Interestingly, the nephron deficit observed in MWF (−36% vs SHR) was linked to RNO6, since total nephron number was only normalized by replacement of RNO6 but not of RNO8 in consomic strains (Table 2).138, 139 Recently, double-consomic studies in MWF-6SHR8SHR by double transfer of SHR-RNO6 and SHR-RNO8 into MWF confirmed a strong synergistic effect between QTL on RNO6 and RNO8, since the albuminuria and associated structural kidney damage phenotypes were completely abolished in the double-consomic strain (Table 2).143
In a reciprocal single-consomic strain, transfer of MWF-RNO8 into the isolated albuminuria-resistant SHR background caused an induction of albuminuria already under normal conditions, while an increase in structural glomerular damage was only detected after Nx in consomic SHR-8MWF (Table 2).144 Thus, the results demonstrate the independent role of MWF QTL on RNO8 for both albuminuria and structural kidney damage.144 In contrast, MWF-RNO6 failed to induce an albuminuria phenotype either under control conditions or in response to a 50% nephron reduction after Nx in consomic SHR-6MWF.145
Sabra rat
Strain breeding
The original Sabra colonies of hypertension-prone (H) and hypertension-resistant (N) strains were developed by Ben-Ishay at the Hebrew University Medical Center in Jerusalem, Israel. Rats were selected for high BP values due to Nx, treatment with deoxycorticosterone acetate, and 1% NaCl.146, 147 This original and not fully inbred colony was terminated in 1992, when a subset of rats was transferred to the Ben-Gurion University Barzilai Medical Center in Ashkelon, Israel. Subsequently, two new genetically and phenotypically homogeneous colonies of Sabra hypertension-prone (SBH/y) and hypertension-resistant (SBN/y) rats were further developed.148
Strain characteristics
The inbred Sabra strains represent a model of salt sensitivity; the substrain SBH/y shows salt sensitivity, while the substrain SBN/y is salt resistant.148, 149 Both inbred Sabra strains are normotensive during life when fed a normal diet, but SBH/y exhibits spontaneously proteinuria,150 whereas SBN/y is protected from proteinuria development.151 After salt loading, salt-sensitive SBH/y animals develop hypertension in contrast to salt-resistant SBN/y rats;151 the SBH/y strain is also more susceptible to develop glomerulosclerosis than SBN/y.151 Moreover, Sabra rats exihbit also a sexual dimorphism of the renal phenotype, since the progression of proteinuria development and FSGS is more accelerated in males compared with females.151
Cosegregation and linkage analyses
Yagil et al.150, 152 performed in two (SBH/y × SBN/y) F2 crosses studied under low-salt diet and after Nx a total genome scan strategy to identify proteinuria QTL. The authors detected in male rats three QTLs linked to proteinura but not to BP on RNO2, RNO17 and RNO20 and in female rats three QTLs linked to proteinuria on RNO11, RNO13 and RNO20 (Tables 1 and 5).150, 152 Moreover, only in males three additional proteinuria QTLs on RNO3, RNO6 and RNO9 were identified at which, however, the SBH/y allele associated with lower albuminuria levels suggesting a protective effect of the SBH/y genome at these QTL (Tables 1 and 5).150, 152
Consomic/congenic studies
Consomic studies on proteinuria development in the Sabra rat model were reported for the identified QTL on RNO2, RNO17 and RN20150, 151 and for two further chromosomes from previous studies, for example, RNO1 and RNOX, on which no proteinuria QTL was mapped by linkage analysis (Table 2).153, 154 In a first report, the transfer of RNO1 or RNO17 from SBH/y into the SBN/y background resulted in both consomic strains in marked proteinuria that was several-fold higher in male animals in response to Nx compared with male SBN/y Nx animals (Table 2).150, 151 These results confirm the role of genes on RNO1 and RNO17 for proteinuria development in male SBH/y rats (Table 3).150, 151 However, the extent of glomerulosclerosis was not considerably influenced by either chromosome.151 In a more recent study, in which the reciprocal single-chromosome transfer from SBN/y into the SBH/y background was used, the functional evidence for the presence of a proteinuria-related QTL on chromosomes RNO1, RNO2 and RNO20 in both male and female rats was confirmed (Table 2).150 In contrast, a significant effect on proteinuria of RNO17 was only detected in males and no effect in either sex was found for RNOX (Table 2).150 Genome-wide gene expression analysis in kidneys from SBH/y and SBN/y with and without uninephrectomy revealed differentially expressed genes that mapped within the boundaries of the proteinuria-related QTLs identified in these strains. Overall 24 transcripts in males and 30 in females were identified, only 4 of which Tubb5 (Tubulin, beta 5 class I), Ubd (Ubiquitin D), Psmb8 (Proteasome (prosome, macropain) subunit, beta type 8 (Large multifunctional peptidase 7)) and C2 (Complement component 2) on RNO20 were common to both sexes (Table 3).150
Spontaneously hypertensive rat
Strain breeding
Okamoto and Aoki155 established the SHR model from outbred WKY rats by selective breeding for high BP under normal conditions in Kyoto, Japan. These not fully inbred stocks were imported by the National Institutes of Health in the United States.16, 156 Subsequently, several colonies were established, which lack genetic homogeneity and thus show phenotypic variance.16, 156, 157, 158
Strain characteristics
The SHR rat is a model that develops spontaneous hypertension in early life.159 The salt sensitivity status of hypertension may vary between different colonies of SHR strains.160, 161 In addition, SHR rats develop several other phenotypes including insulin resistance,162, 163, 164, 165 renal damage such as mild proteinuria and albuminuria, glomerular sclerosis and pathological alterations in small vessels with age.166, 167
Cosegregation and linkage analyses
Herring et al.168 investigated whether the IgG/Fc-γ receptor pathway in glomeruli is capable of modulating hypertensive glomerular disease such as albuminuria in SHR. In an (SHR-A3 × SHR-B2)-F2 intercross, the authors identified in male SHR-A3 a QTL on RNO6 linked to IgG subclasses (Tables 1 and 5), which was derived from the IgH gene (immunoglobulin heavy chain complex).168 Subsequently, single-nucleotide polymorphism genotyping revealed that allelic variation in the IgH haplotype block or neighboring genes may modify the susceptibility to hypertensive renal injury without a BP influence.168
Congenic studies
Renal transplant studies showed that the kidneys of BN are more susceptible to hypertension-induced damage compared with SHR.169 St Lezin et al.170 assumed that underlying genetic susceptibility factors, that is, the Rf loci on RNO1, which were originally identified in the FHH rat,77, 89, 90 may contribute to renal failure in BN.170 Subsequently, the authors introgressed a 22-cM segment of RNO1, which may overlap with Rf-2, Bpfh-1 and possibly with Rf-1 in FHH,77, 89, 90 from normotensive BN/Cr rats into the hypertensive SHR/Ola background of the congenic strain SHR.BN-D1Mit3/Igf2 (Tables 2 and 3).170 The results in these strains demonstrated that in BN rats susceptibility to renal damage such as proteinuria and glomerular injury in response to deoxycorticosterone acetate-salt loading was also significantly aggravated by one or more genes related to the transferred RNO1 segment, carrying Rf loci from FHH (Table 2).170
Spontaneously hypertensive rat, stroke-prone
Strain breeding
By Okamoto et al.171 the A1-sb and A3 substrains of SHR were crossed to select offsprings for further inbreeding, when parents were highly susceptible to stroke.172 The resulting inbred strain SHRSP/A3N was defined as SHRSP.171
Strain characteristics
SHRSP show salt-sensitive spontaneous hypertension, vascular and particularly cerebrovascular lesions associated with a high incidence of strokes.160, 171, 173, 174 In addition, SHRSP develop salt-induced renal damage such as albuminuria,48 severe glomerulosclerosis, tubuloinsterstitial fibrosis, inflammation,48, 160 renal vascular lesions,173 and an increase in the glomerular renin-angiotensin system.175 Male SHRSP rats are more affected in developing renal lesions compared with females.176
Cosegregation and linkage analyses
In a genotype/phenotype cosegregation study in an SHRSP/SHR F2 intercross population including both genders, Gigante et al.176 detected QTL regions on RNO1, RNO4, RNO10 and RNO16 affecting renal damage in this cross (Tables 1 and 5), while both susceptible and protective alleles of SHRSP were identified for renal changes such as the degree of renal vascular and parenchymal lesions.
Consomic studies
On RNO1 several QTLs linked to BP,47, 48, 54, 77, 90, 177, 178, 179, 180, 181, 182, 183 stroke or stroke-associated phenotypes,182, 184 and renal damages48, 54, 77, 90, 141, 142, 151 could be identified in different rat models. To demonstrate genetic differences in the incidence of hypertension, cerebral stroke and renal damage under salt loading in tap water (1% NaCl), Ishikawa et al.185 analysed five congenic rat strains, in which different chromosomal segments from WKY/Izm-RNO1 were transferred into the SHRSP/Izm background (Table 2). The findings showed that one or more gene(s) on RNO1 was/were associated with salt-induced renal damage, that is, albuminuria and glomerulosclerosis, which act independently of BP in SHRSP.
Conclusions
The increasing incidence and prevalence of complex forms of CKD in the general human population1, 2, 3, 4, 5, 9 poses a major global health problem. Understanding the molecular basis, including the genetic susceptibility, of complex CKD may therefore open new opportunities for early diagnosis and development of novel therapeutic strategies that protect against CKD, halt CKD or even reverse the apparently inevitable progressive course of CKD.186 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.187 Notwithstanding this progress, knowledge about genetic factors that contribute to common forms of complex CKD is scarce, although human genome-wide association studies sought to close this gap by identifying susceptibility loci for CKD or reduced kidney function, that is, GFR.99, 188, 189 So far susceptibility loci could be identified on all human chromosomes (HSA), 1–22, except the sex chromosomes.2, 3, 8, 99, 188, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201 Only a few studies, however, were successful, identifying within their associated genomic interval a single locus with a plausible candidate as a susceptibility locus for more common forms of CKD. Thus, a locus on chromosome 22 carrying a variant in the Apolipoprotein L-1 (APOL1) gene has been shown to explain a major portion of the increased genetic risk for non-diabetic CKD observed in African Americans.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 rat19 and Rab38 in the FHH rat104, 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.1, 2, 3, 4, 5, 9 In this regard, this panel is a valuable experimental and data resource in which numerous QTLs associated with renal (disease) phenotypes have been identified on all rat chromosomes (Tables 4 and 5). Moreover, several important findings obtained from studies in these models have already contributed to our knowledge on the genetic determination of complex renal disease phenotypes. Hence, studies in the FHH,90, 93, 95, 97 MWF141, 142, 143 and SS53, 54 rat models highlighted the role of major susceptibility loci that in concert and genetic interaction with multiple other loci influence renal disease susceptibility (Table 5). Moreover, these models allow the combination of genetic analyses with unlimited gene expression studies,65, 70, 150 including timed renal and compartment-specific expression analysis during the onset of renal disease phenotypes such as albuminuria,143, 204 while these experimental algorithms are difficult or impossible to pursue in humans due to the limited access to renal tissue. The comprehensive exploitation of the genotype–renal phenotype associations that are inherited in this panel of rat strains is therefore suitable for making a significant contribution to the development of an integrated approach to the systems genetics of CKD.189 This may pave the way for the development of eagerly awaited novel and successful prognostic, diagnostic and therapeutic tools for the integrated management of common forms of CKD.
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Acknowledgements
This study was supported by the Deutsche Hochdruckliga (DHL®) Hypertensiologie Professur to RK and by grants from the DFG KR1152-3-1 and SCHU 2604/1-1.
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Schulz, A., Kreutz, R. Mapping genetic determinants of kidney damage in rat models. Hypertens Res 35, 675–694 (2012). https://doi.org/10.1038/hr.2012.77
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DOI: https://doi.org/10.1038/hr.2012.77
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