Received March 7, 2006
Accepted on October 23, 2006

BASIC SCIENCE: Genetics and Development

Development of Overt Proteinuria in the Munich Wistar Frömter Rat Is Suppressed by Replacement of Chromosome 6 in a Consomic Rat Strain

Angela Schulz ^*, Judith Weiss ^*, Maria Schlesener ^*, Jonna Hänsch ^*, Markus Wehland ^*, Norbert Wendt ^*, Peter Kossmehl ^*, Anika Sietmann , Daniela Grimm ^*, Monika Stoll , Jens Randel Nyengaard , and Reinhold Kreutz ^*1

*Institut für Klinische Pharmakologie und Toxikologie, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, and Leibniz-Institut für Arterioskleroseforschung, Münster, Germany; and Stereology and Electron Microscopy Research Laboratory and MIND Center, University of Aarhus, Aarhus, Denmark

¹ To whom correspondence should be addressed. E-mail: reinhold.kreutz{at}charite.de.

	Abstract

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.