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

Kyoungmi Kim, Craig H Warden, Stephen M Griffey, Jose G. Vilches-Moure, Susan Hansen, Edwin Cuppen, Isaäc J. Nijman, Sally Chiu, Judith S. Stern

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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 Leprfa/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. We killed 237 BZZ backcross animals at 15 wk 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 wk 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 Brown Norway rats showed no evidence for these changes. Thus, by removing the influence of the Leprfa/fa mutation from analysis we have identified UAE QTLs unlinked to LEPR.

Original languageEnglish (US)
Pages (from-to)297-305
Number of pages9
JournalPhysiological Genomics
Volume41
Issue number3
DOIs
StatePublished - 2010

Keywords

  • Epistasis
  • Obesity
  • Quantitative trait loci
  • Renal
  • Urinary albumin excretion

ASJC Scopus subject areas

  • Physiology
  • Genetics
  • Medicine(all)

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    Kim, K., Warden, C. H., Griffey, S. M., Vilches-Moure, J. G., Hansen, S., Cuppen, E., Nijman, I. J., Chiu, S., & Stern, J. S. (2010). Genes unlinked to the leptin receptor influence urinary albumin excretion in obese Zucker rats. Physiological Genomics, 41(3), 297-305. https://doi.org/10.1152/physiolgenomics.90367.2008