Development of overt proteinuria in the Munich Wistar Frömter rat is suppressed by replacement of chromosome 6 in a consomic rat strain.
In a cross between the Munich Wistar Frömter (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.
Schulz
Angela
A
Institut für Klinische Pharmakologie und Toxikologie, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Weiss
Judith
J
Schlesener
Maria
M
Hänsch
Jonna
J
Wehland
Markus
M
Wendt
Norbert
N
Kossmehl
Peter
P
Sietmann
Anika
A
Grimm
Daniela
D
Stoll
Monika
M
Nyengaard
Jens Randel
JR
Kreutz
Reinhold
R
D000419:Albuminuria / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D020296:Animals, Congenic; D001483:Base Sequence; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D007668:Kidney / Q000473:pathology; D008297:Male; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D011922:Rats, Mutant Strains; D017208:Rats, Wistar
D017931:DNA Primers