Abstract-The inherited nephron deficit and progressive albuminuria development observed in hypertensive MunichWistar Frömter (MWF) rats are influenced by quantitative trait loci on rat chromosome (RNO) 6 and RNO8. Previous studies in young MWF rats suggested that the nephron deficit represents a cause for glomerular hypertrophy preceding onset of albuminuria at 8 weeks and demonstrated a simultaneous induction of the podocyte stress marker desmin and podoplanin loss in podocytes. Key Words: genetics Ⅲ albuminuria Ⅲ glomerular damage Ⅲ podocyte Ⅲ consomic rat A lbuminuria is an important independent predictor for progression of both renal and cardiovascular disease and also of mortality risk in patients with hypertensive diabetes mellitus and even in the general population. 1,2 Previous reports have shown that the genetic predisposition for development of albuminuria is complex and multifactorial. [3][4][5][6][7] The Munich Wistar Frömter (MWF) rat is a suitable animal model to investigate the genetic and molecular mechanisms related to early development of albuminuria. MWF rats demonstrate an inherited nephron deficit and mild hypertension and develop at young age spontaneous albuminuria followed by progressive proteinuria in aging animals. 8,9 In previous studies we have shown that increased urinary albumin excretion (UAE) in MWF rats is largely determined by quantitative trait loci on rat chromosome (RNO) 6 and RNO8, respectively. 10,11 In these studies we used the spontaneously hypertensive rat (SHR) as a contrasting reference strain with lowgrade UAE 12 and transferred in separate experiments either the entire chromosome 6 or 8 from SHRs into the MWF genetic background. The resulting consomic rat strains, that is, , demonstrated both a marked suppression of early albuminuria development compared with the MWF strain, thus providing evidence for the functional relevance of genes on RNO6 and RNO8 for albuminuria, respectively. 10,11 IJpelaar et al 13 showed previously that onset of albuminuria in young MWF animals is already preceded by glomerular hypertrophy and coincided with focal and segmental loss of podoplanin and de novo expression of desmin in affected podocytes when compared with SHRs. 13 The genes coding for desmin and podoplanin map to RNO9 and RNO5 and can, therefore, be ruled out as positional candidate genes for the 2 important albuminuria quantitative trait loci on RNO6 and

A major quantitative trait locus (QTL) on rat chromosome (RNO)6 was linked to albuminuria in Munich Wistar Frömter rats (MWF). We tested whether transfer of MWF RNO6 into the background of albuminuria-resistant spontaneously hypertensive rats (SHR) induces albuminuria in consomic SHR-6(MWF) animals. Male MWF, SHR, and SHR-6(MWF) were sham operated and treated between 6 and 24 wk of age with normal water (Sham) or with water containing 20 mg/l N(G)-nitro-L-arginine methyl ester (L-NAME) or unilaterally nephrectomized (Nx). Compared with SHR albuminuria was not increased in SHR-6(MWF) in both Sham and Nx groups. All animals survived the observation period in Sham and Nx groups, while premature mortality occurred from 12-14 wk on in L-NAME-treated SHR and SHR-6(MWF) compared with MWF L-NAME animals, in which survival was not affected (P < 0.005, respectively). Subsequent further analysis of L-NAME-treated animals at 12 wk of age showed significantly increased arterial blood pressures in both SHR and SHR-6(MWF) compared with control (P < 0.05), with higher levels in SHR compared with consomics (P < 0.05). However, L-NAME-treated consomic animals demonstrated increased albuminuria compared with SHR (12.7 +/- 3.5 vs. 0.8 +/- 0.2 mg/24 h; P < 0.05) and an induction of tubulointerstitial structural injury and expression of neutrophil gelatinase-associated lipocalin mRNA (P < 0.05 vs. other strains). Our study demonstrates that isolation of the RNO6 albuminuria QTL from the MWF background and transfer into SHR fails to induce an albuminuria phenotype during normal conditions or after nephron reduction. Moreover, our data indicate that genes on RNO6 contribute to the development of L-NAME-induced renal damage in the SHR strain.