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...

Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease. Albuminuria is a risk factor for FSGS and is influenced by environmental, genetic, and sex-specific factors. Podocytes play a central role in the development of albuminuria, but the precise relationship between early glomerular and podocyte-associated damage and albuminuria is unclear. Furthermore, experimental findings demonstrate a sex difference in development of albuminuria and FSGS. We investigated the early glomerular changes in male Munich-Wistar-Frömter (MWF) rats, which spontaneously develop albuminuria, and male albuminuria-resistant spontaneously hypertensive rats (SHR). In addition, since female MWF rats are protected from overt proteinuria and progressive renal disease, we compared the phenotypic changes in podocytes during early development of albuminuria in male and female MWF rats. In male MWF rats, glomerular hypertrophy preceded the onset of albuminuria and was greater than in male SHR. Albuminuria developed starting at 6 wk of age and coincided with focal and segmental loss of podoplanin, increased expression of desmin, entrapment of albumin in affected podocytes, and focal and segmental foot process effacement at the ultrastructural level. Other podocyte-associated molecules, such as nephrin and zonula occludens 1, were unaffected. Early glomerular hypertrophy and podocyte damage did not differ between male and female MWF rats. Our data show for the first time that albuminuria in male and female MWF rats is preceded by glomerular hypertrophy and accompanied by focal and segmental loss of podoplanin when FSGS was not yet present.

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.