Brown Norway Chromosome 1 Congenic Reduces Symptoms of Renal Disease in Fatty Zucker Rats

Abstract

We previously reported that a congenic rat with Brown Norway (BN) alleles on chromosome 1 reduces renal disease of 15-week old fatty Zucker rats (ZUC). Development of renal disease in fatty BN congenic and fatty ZUC rats from 9 through 28 weeks is now examined. Analysis of urine metabolites by 1H nuclear magnetic resonance (NMR) spectroscopy revealed a significantly increased urinary loss of glucose, myo-inositol, urea, creatine, and valine in ZUC. Food intake was lower in the BN congenic rats at weeks 9–24, but they weighed significantly more at 28 weeks compared with the ZUC group. Fasting glucose was significantly higher in ZUC than congenic and adiponectin levels were significantly lower in ZUC, but there was no significant genotype effect on Insulin levels. Glucose tolerance tests exhibited no significant differences between ZUC and congenic when values were normalized to basal glucose levels. Quantitative PCR on livers revealed evidence for higher gluconeogenesis in congenics than ZUC at 9 weeks. Plasma urea nitrogen and creatinine were more than 2-fold higher in 28-week ZUC. Twelve urine protein markers of glomerular, proximal and distal tubule disease were assayed at three ages. Several proteins that indicate glomerular and proximal tubular disease increased with age in both congenic and ZUC. Epidermal growth factor (EGF) level, a marker whose levels decrease with distal tubule disease, was significantly higher in congenics. Quantitative histology of 28 week old animals revealed the most significant genotype effect was for tubular dilation and intratubular protein. The congenic donor region is protective of kidney disease, and effects on Type 2 diabetes are likely limited to fasting glucose and adiponectin. The loss of urea together with a small increase of food intake in ZUC support the hypothesis that nitrogen balance is altered in ZUC from an early age.

Chow fed UC Davis strain female Lepr fatty Zucker rats exhibit mild glucose intolerance, hypertriglyceridemia, and increased urine volume, all reduced by a Brown Norway strain chromosome 1 congenic donor region

“…Chow-fed males develop a mild form of T2D, have significantly elevated plasma triglycerides and develop phenotypes of mild to moderate renal disease [ 13 ]. In the UC Davis male ZUC colony, T2D related traits were primarily the presence of glucose in urine and elevated fasted glucose levels [ 9 , 14 , 15 ]. Renal disease markers included increases of urinary albumin excretion and urine volume with age [ 14 ].…”

“…In the UC Davis male ZUC colony, T2D related traits were primarily the presence of glucose in urine and elevated fasted glucose levels [ 9 , 14 , 15 ]. Renal disease markers included increases of urinary albumin excretion and urine volume with age [ 14 ]. Our previous studies have demonstrated that ovariectomy decreases and estrogen increases urinary albumin excretion in female UC Davis Zucker rats [ 16 ].…”

“…Phenotype differences between congenic and background are due to donor strain alleles in the selected chromosomal region. We previously reported the development of a congenic strain that has Brown Norway (BN) alleles on the distal half of chromosome 1 on a UC Davis ZUC background [ 14 ]. The formal name for the congenic is BN.ZUC- D1Rat183 - D1Rat90 where D1Rat183 and D1Rat90 are microsatellite markers polymorphic between the UC Davis ZUC and the Brown Norway rat strain.…”

“…The formal name for the congenic is BN.ZUC- D1Rat183 - D1Rat90 where D1Rat183 and D1Rat90 are microsatellite markers polymorphic between the UC Davis ZUC and the Brown Norway rat strain. The congenic strain will be referred to as BN congenic throughout the rest of this paper [ 14 , 15 ]. Thus, BN congenic fatty animals are homozygous for Lepr faSte and have the BN donor region from D1Rat183 - D1Rat90 on a ZUC background.…”

“…Thus, BN congenic fatty animals are homozygous for Lepr faSte and have the BN donor region from D1Rat183 - D1Rat90 on a ZUC background. We previously demonstrated that the BN chromosome 1 congenic donor region decreased both T2D and renal disease in chow-fed fatty males compared to ZUC background [ 14 ]. These data are consistent with the donor region influencing T2D and renal disease.…”