Genes unlinked to the leptin receptor influence urinary albumin excretion in obese Zucker rats.

Authors: Kim, K  Warden, CH  Griffey, SM  Vilches-Moure, JG  Hansen, S  Cuppen, E  Nijman, IJ  Chiu, S  Stern, JS 
Citation: Kim K, etal., Physiol Genomics. 2010 Feb 16.
Pubmed: (View Article at PubMed) PMID:20159938
DOI: Full-text: DOI:10.1152/physiolgenomics.90367.2008

We have previously shown that 90% of outbred obese Zucker Lepr(fa/fa) rats die prematurely of renal disease. Thus, renal disease in obese Zucker Lepr(fa/fa) rats may be caused by the LEPR mutation on chromosome 5, by the obesity, or it may be influenced by Zucker susceptibility alleles of genes on other chromosomes. We have searched for susceptibility genes on other chromosomes using urinary albumin excretion (UAE) as an early indicator of altered renal function in a backcross of (Brown Norway x inbred Zucker) F1 x inbred Zucker, which we name the BZZ cross. 237 BZZ backcross animals were sacrificed at 15 weeks of age. All included animals were homozygous for the fatty mutation of LEPR and were obese. Urinary creatinine measurements were used to calculate the Albumin to Creatinine Ratio (ACR). We identified direct effect quantitative trait loci (QTLs) for UAE and ACR on Chromosome 1 (LOD scores = 3.6 and 2.86, respectively) in males, and Chromosome 4 (LOD score = 2.9) in females. Significant QTLs were identified for left kidney weight for females on Chromosomes 3 and 12. We also demonstrated that kidneys from 15 week old obese inbred Zucker rats already show evidence of kidney pathology: tubular dilation, proteinaceous fluid accumulation, evidence for inflammation, and mild mesangial and tubular membrane basement membrane thickening. Both lean Zucker rats and the BN rats showed no evidence for these changes. Thus, by removing the influence of the Lepr(fa/fa) mutation from analysis we have identified UAE QTLs unlinked to LEPR. Key words: urinary albumin excretion, Zucker, kidney, UAE.

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