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...

Schulz A, Hänsch J, Kuhn K, Schlesener M, Kossmehl P, Nyengaard JR, Wendt N, Huber M, Kreutz R. Nephron deficit is not required for progressive proteinuria development in the Munich Wistar Frömter rat.

Clinical and experimental studies indicate that the progression of renal disease is faster in males than females. These observations are corroborated by a sexual dimorphism observed in the polygenetic MWF (Munich Wistar Frömter) rat model. The age-dependent spontaneous progression of increased UAE (urinary albumin excretion) in male MWF rats is influenced by multiple QTLs (quantitative trait loci). In contrast, female MWF rats only develop a slight increase in UAE, while the role of genetic factors for this phenotype is unknown. In the present study, we show that, compared with resistant SHRs (spontaneously hypertensive rats), both male and female MWF rats develop a significant increase in UAE at 24 weeks of age (P<0.0001), although blood pressures were lower compared with SHRs (P<0.0001). UAE was significantly higher in male (7-fold) compared with female MWF rats (162.6+/-15.9 compared with 24.0+/-5.5 mg/24 h respectively; P<0.0001), and only male MWF rats developed significant glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.0001). To test the role of genetic factors in the development of low grade albuminuria in female MWF rats, we analysed the role of a major UAE QTL on rat chromosome 6. To this end, we analysed a consomic MWF-6(SHR) strain in which chromosome 6 from SHRs was introgressed into the MWF rat background. Time course analysis of UAE in females indicated that the small increase in UAE in MWF rats was fully suppressed by exchange of rat chromosome 6. Thus, taken together with previous studies in males, we show that RNO6 protects against the increase in albuminuria with age in both female and male MWF rats.

Our findings point to a link between hypercholesterolemia and LV fibrosis in salt-sensitive hypertension of SS rats which is genetically modulated by RNO19.

Background: We investigated whether alterations of transient receptor potential canonical (TRPC) channel expression may be observed in tissues from Munich Wistar Frömter (MWF) rats showing proteinuria compared to control Wistar rats. Methods: TRPC expression was investigated in tissue from MWF and Wistar rats using quantitative real time PCR, immunoblotting, and immunohistochemistry. Results: Compared to Wistar rats MWF rats showed significantly increased systolic blood pressure and significantly higher left ventricle weight (each p < 0.01). Quantitative real time PCR revealed that TRPC3 transcripts were significantly higher in kidney cortex from MWF rats compared to Wistar rats (p < 0.01). TRPC3 transcripts were not significantly different in kidney medulla nor in aorta from both groups (p = n.s.). Furthermore, TRPC6 transcripts were significantly lower in kidney cortex from MWF rats compared to Wistar rats (p < 0.001). Immunoblotting showed that TRPC3 channel protein expression was also significantly higher in kidney cortex from MWF rats compared to Wistar rats (p < 0.01). There was a significant correlation of TRPC3 mRNA and a specific marker for endothelium, von Willebrand factor (vWF; Spearman r = 0.564; p < 0.01). We observed a significant correlation between the TRPC3 transcripts to TRPC6 transcripts ratio in kidney cortex and urinary albumin excretion (Spearman r = 0.785, p < 0.001). Conclusion: Altered TRPC expression pattern in kidney cortex is associated with kidney damage in MWF rats showing hypertension and albuminuria.