Protective effect of female gender on the development of albuminuria in a polygenetic rat model is enhanced further by replacement of a major autosomal QTL

Abstract

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.

Mapping genetic determinants of kidney damage in rat models

“…141,142 Consomic studies The functional role of both major albuminuria QTLs on RNO6 and RNO8 was confirmed by transfer of either RNO6 or RNO8 from SHR into the MWF background. [138][139][140] Thus, in both single-consomic strains MWF-6 SHR and MWF-8 SHR , the progressive albuminuria observed in aging male and female MWF was significantly ameliorated (Table 2). [138][139][140] Interestingly, the nephron deficit observed in MWF ( À36% vs SHR) was linked to RNO6, since total nephron number was only normalized by replacement of RNO6 but not of RNO8 in consomic strains (Table 2).…”

“…[138][139][140] Thus, in both single-consomic strains MWF-6 SHR and MWF-8 SHR , the progressive albuminuria observed in aging male and female MWF was significantly ameliorated (Table 2). [138][139][140] Interestingly, the nephron deficit observed in MWF ( À36% vs SHR) was linked to RNO6, since total nephron number was only normalized by replacement of RNO6 but not of RNO8 in consomic strains (Table 2). 138,139 Recently, double-consomic studies in MWF-6 SHR 8 SHR by double transfer of SHR-RNO6 and SHR-RNO8 into MWF confirmed a strong synergistic effect between QTL on RNO6 and RNO8, since the albuminuria and associated structural kidney damage phenotypes were completely abolished in the double-consomic strain (Table 2).…”

“…[130][131][132][133][134][135][136][137][138][139] Moreover, a sexual dimorphism leads to a more severe manifestation and progression of albuminuria and subsequent renal failure in males compared with females. 130,133,140 Cosegregation and linkage analyses Schulz et al performed two genome-wide linkage analyses in backcross populations between MWF and a normotensive (Lewis/ FUB ) and a hypertensive (SHR/ FUB ) reference strain and identified overall 11 different QTLs on 10 rat chromosomes including RNO1 (QTL1 and QTL2), RNO4, RNO6-RNO9, RNO12, RNO15, RNO17 and RNOX, which accounted for albuminuria development in MWF (Tables 1 and 5). 130,141,142 In addition, six QTLs on RNO1 (QTL1 and QTL2), RNO6, RNO8, RNO15 and RNO17 were linked to proteinuria, and one QTL was linked to renal interstitial fibrosis on RNO6 (Tables 1 and 5).…”

Nephron deficit is not required for progressive proteinuria development in the Munich Wistar Frömter rat

“…In addition, MWF develop an early increase in albuminuria and progressive proteinuria as well as glomerulosclerosis with age (4,26). Interestingly, despite the fact that the nephron deficit is similar in male and female MWF animals (4) they demonstrate a sex-specific difference in the development of progressive albuminuria and glomerulosclerosis, which is much more pronounced in males (4,24). In previous work we showed that the development of overt and mild albuminuria in males and females is markedly suppressed in the consomic MWF-6 SHR strain (26).…”

“…In previous work we showed that the development of overt and mild albuminuria in males and females is markedly suppressed in the consomic MWF-6 SHR strain (26). In this consomic strain we replaced a major albuminuria quantitative trait locus (QTL) by transfer of rat chromosome (RNO) 6 from albuminuria-resistant spontaneously hypertensive rat (SHR) into the MWF genetic background (24,26). Importantly, the congenital nephron deficit of MWF was also abolished by transfer of RNO6, which thus provided further evidence for a pathophysiological link between the inherited nephron deficit and albuminuria development in MWF.…”