These results suggest a reduced efficiency of nephron induction in MWF rats during the early stages of nephrogenesis that is partially dependent on genetic loci on RNO6. In addition, Hgf that maps to RNO4 may represent an interesting candidate gene that contributes to the nephron deficit in MWF rats.

Inbred Munich Wistar Frömter [MWF/FubRkb (RGD:724569), MWF] rats develop progressive albuminuria with age that is under polygenetic influence. We previously identified a major albuminuria quantitative trait locus (QTL) on rat chromosome (RNO)8 in MWF. To test the independent role of QTL(s) for albuminuria development on RNO8, we generated a consomic SHR-Chr 8(MWF)/Rkb (SHR-8(MWF)) strain by transferring RNO8 from MWF into the albuminuria-resistant background of the spontaneously hypertensive rat [SHR/FubRkb (RGD:631696; SHR)]. Young male MWF, SHR, and SHR-8(MWF) were sham-operated or unilaterally nephrectomized (Nx) at 6 wk and followed up to 24 wk of age, respectively. Systolic blood pressure was significantly lower in SHR-8(MWF) Sham compared with SHR Sham (-19.4 mmHg, P = 0.03) at 24 wk. In contrast, transfer of MWF-RNO8 into SHR induced a significant elevation of urinary albumin excretion (UAE) between weeks 12 and 24 in SHR-8(MWF) compared with SHR Sham animals (P < 0.0001, respectively). Nx resulted in a significant increase in UAE in both strains during follow-up (P < 0.0001, respectively), with significant higher values in SHR-8(MWF) compared with SHR (P < 0.005, respectively). Renal structural changes as determined by glomerulosclerosis (GSI) and tubulointerstitial damage index (TDI) were significantly higher in consomic animals either at Sham (TDI) or Nx (GSI) conditions (P < 0.05, respectively). These data confirm the independent role of MWF QTL(s) on RNO8 for both albuminuria and structural kidney damage. Moreover, this study shows for the first time the induction of albuminuria by transferring one or more albuminuria QTL into a resistant recipient background in a consomic rat strain.

The blood pressure increase and impaired survival of SHRs in response to nitric oxide inhibition is profoundly influenced by genes on RNO8.

Munich Wistar Frömter (MWF) rats develop spontaneous albuminuria that is linked to autosomal genetic loci and inherit a nephron deficit in both female and male animals, respectively. However, albuminuria and kidney damage are clearly more pronounced in males. Here we tested whether androgens and the androgen receptor influence albuminuria in male MWF. We first demonstrated in a pilot study that orchiectomy (Ox) of male MWF led to a significant suppression of urinary albumin excretion (UAE), while continuous testosterone supplementation in MWF Ox led to UAE levels similar to sham-operated (Sham) MWF rats. Subsequently, we performed a comparative main study between male MWF and normal Wistar rats to evaluate the effect of the androgen receptor on UAE development in adult animals up to the age of 18 wk. MWF Sham developed a marked increase in UAE compared with Wistar Sham (48.30 ± 6.16 vs. 0.42 ± 0.08 mg/24 h, P < 0.0001). UAE was significantly lower in MWF Ox compared with MWF Sham (-55%, P < 0.0001). In MWF Ox animals supplemented with testosterone and treated with the androgen receptor antagonist flutamide (OxTF) UAE at 18 wk was even lower compared with MWF Ox (-71%, P < 0.01) and similar to age-matched female MWF. The mRNA expression of renal tubular injury markers Kim1 and NGAL was increased in MWF Sham compared with Wistar Sham (P < 0.0008, respectively) and expression decreased significantly in MWF OxTF (P < 0.0004, respectively). Thus, the sexual dimorphism in albuminuria development in MWF can be attributed to testosterone and the androgen receptor in male rats.