Development of Overt Proteinuria in the Munich Wistar Fro[Combining Diaeresis]mter Rat Is Suppressed by Replacement of Chromosome 6 in a Consomic Rat Strain

Abstract

In a cross between the Munich Wistar Frö mter (MWF) rat and spontaneously hypertensive rats (SHR), a major quantitative trait locus (QTL) was identified on rat chromosome 6 (RNO6) that demonstrated the strongest linkage to albuminuria among several QTL identified. The QTL represented the only locus that is linked to both early-onset albuminuria and increased renal interstitial fibrosis in adult animals. A consomic MWF-6 SHR strain in which chromosome 6 from SHR was introgressed into the MWF background therefore was generated to test the relevance of this QTL. Phenotype analysis at 8 wk of age revealed that early onset of albuminuria in MWF with a 55-fold elevation of urinary albumin excretion compared with SHR (P < 0.0001) was completely abolished in MWF-6 SHR . Time-course analysis until week 24 demonstrated only a moderate increase of urinary albumin excretion in MWF-6 SHR , whereas MWF reached levels in the nephrotic range (16.6 ؎ 3.5 versus 162.6 ؎ 16.0 mg/24 h; P < 0.0001). At this age, analysis of glomerulosclerosis, tubulointerstitial damage, renal interstitial fibrosis, and renal collagen III mRNA expression revealed a significant improvement of all parameters in MWF-6 SHR compared with MWF (P < 0.05). At 32 wk, MWF but not MWF-6 SHR demonstrated overt proteinuria (354.6 ؎ 37.6 versus 48.8 ؎ 13.2; P < 0.0001), whereas serum urea, cholesterol, and triglyceride concentrations were lower and creatinine clearance was higher in MWF-6 SHR compared with MWF (P < 0.05). Therefore, although albuminuria in MWF is determined by a complex interplay of several QTL, our data demonstrate that genetic exchange of one locus on RNO6 leads to marked suppression of early-onset albuminuria and renal damage in MWF. 18: 113-121, 200718: 113-121, . doi: 10.1681 A n elevated urinary albumin excretion (UAE) rate is a predictor for the development of chronic nephropathy, and a moderate increase of UAE in the range of microalbuminuria represents an independent risk factor for cardiovascular events in the general population, in arterial hypertension, and particularly in patients with diabetes or documented cardiovascular disease (1-4). Albuminuria and proteinuria are complex phenotypes that are influenced by both environmental and genetic factors (5-7). Elevated UAE rates represent a hallmark of diabetic nephropathy (7), and previous genetic segregation analysis of UAE in families with type 2 diabetes demonstrated that levels of UAE are determined by mixture of probably recessive genes with large and small effect in individuals both with and without diabetes (8,9). More recently, genetic analyses in extended families confirmed that similar genes contribute to the heritability of UAE in family members with and without diabetes (7). Moreover, several quantitative trait loci (QTL) have been identified by genomewide linkage analyses for UAE in diabetes, hypertension, and the general population (6,7,10). J Am Soc NephrolPrevious studies in hypertensive genetic rat models have shown that elevated UAE levels are also influenced by several...

Mapping genetic determinants of kidney damage in rat models

“…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-6 SHR and MWF-8 SHR , 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 ( À36% 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][140] Thus, in both single-consomic strains MWF-6 SHR and MWF-8 SHR , 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 ( À36% 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-6 SHR 8 SHR 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).…”

“…[138][139][140] Interestingly, the nephron deficit observed in MWF ( À36% 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-6 SHR 8 SHR 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-8 MWF (Table 2).…”

“…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).…”

Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease

“…To date, complete genome scans have been performed on 13 experimental crosses, identifying more than 40 quantitative trait loci (QTLs) linked to proteinuria alone (Supplemental Table 4). Many of the QTLs have been confirmed and the chromosomal locations further refined using congenic strain analysis, [33][34][35][36][37][38][39][40] a method more often used in the rat. Congenic strains are developed by transferring an entire chromosome (or chromosomal segment) from one strain onto the genetic background of another through an iterative breeding paradigm that continues until the QTL interval is reduced to contain a relatively small set of genes, allowing for a detailed analysis of each individual gene contained in the linked region.…”