TY - JOUR
T1 - Genes unlinked to the leptin receptor influence urinary albumin excretion in obese Zucker rats
AU - Kim, Kyoungmi
AU - Warden, Craig H
AU - Griffey, Stephen M
AU - Vilches-Moure, Jose G.
AU - Hansen, Susan
AU - Cuppen, Edwin
AU - Nijman, Isaäc J.
AU - Chiu, Sally
AU - Stern, Judith S.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Epistasis
KW - Obesity
KW - Quantitative trait loci
KW - Renal
KW - Urinary albumin excretion
UR - http://www.scopus.com/inward/record.url?scp=77952908117&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952908117&partnerID=8YFLogxK
U2 - 10.1152/physiolgenomics.90367.2008
DO - 10.1152/physiolgenomics.90367.2008
M3 - Article
C2 - 20159938
AN - SCOPUS:77952908117
VL - 41
SP - 297
EP - 305
JO - Physiological Genomics
JF - Physiological Genomics
SN - 1094-8341
IS - 3
ER -