RGD Reference Report - Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats. - Rat Genome Database

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Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats.

Authors: Tofovic, S P  Kusaka, H  Kost, C K  Bastacky, S 
Citation: Tofovic SP, etal., Ren Fail. 2000;22(4):387-406. doi: 10.1081/jdi-100100882.
RGD ID: 401965414
Pubmed: PMID:10901178   (View Abstract at PubMed)
DOI: DOI:10.1081/jdi-100100882   (Journal Full-text)

The obese ZDFxSHHF-fa/fa(cp) model was developed by crossing lean female Zucker Diabetic Fatty (ZDF +/fa) and lean male Spontaneously Hypertensive Heart Failure (SHHF/Mcc-fa(cp), +/fa) rats. The purpose of the present study was to determine renal function and morphology, hemodynamics, and metabolic status in ZDFxSHHF rats. Two sets of experiments were conducted. First, we evaluated heart and kidney function and metabolic status in aged (46 weeks old) male obese ZDFxSHHF and age matched obese SHHF rats, lean Spontaneously Hypertensive (SHR) and lean normotensive Wistar Kyoto (WKY) rats. In the second set of experiments, renal function and structure as well as metabolic and lipid status were determined in lean (LN) and obese (OB) adult (29-weeks of age) ZDFxSHHF rats. At 46 weeks of age ZDFxSHHF rats are hypertensive expressing marked cardiac hypertrophy associated with diastolic dysfunction and preserved contractile function. Fasted hyperglycemia and hyperinsulinemia are accompanied by moderate hypercholesterolemia and hypertriglyceridemia. Obese aged ZDFxSHHF have marked renal hypertrophy, a 3-8 fold decrease in creatinine clearance (compared with SHHF, SHR and WKY), a high percent of segmental + global glomerulosclerosis (59.8%+/-10.8), and severe tubulointerstitial and vascular changes. Obese ZDFxSHHF rats die at an early age (approximately 12 months) from end-stage renal failure. Studies conducted in 29-week animals showed that, although both LN and OB 29-week old animals are hypertensive, OB animals have more severely compromised renal function and structure as compared with lean litter-mates (kidney weight: 2.56+/-0.16 vs. 1.61+/-0.12 g; creatinine clearance: 0.42+/-0.04 vs. 1.24+/-0.13 L/g kid/day; renal vascular resistance 12.39+/-1.4 vs. 6.14+/-0.42 mmHg/mL/min/g kid; protein excretion: 556+/-16 vs. 159+/-9mg/day/g kid, p < 0.05, OB vs. LN, respectively). Obesity is also associated with hyperglycemia (424+/-37 vs. 115+/-11 mg/dL), hyperinsulinemia (117.2+/-8.8 vs. 42.3+/-3.5 microU/mL), hypertriglyceridemia (5200+/-702 vs. 194+/-23 mg/dL), hypercholesterolemia (632+/-39 vs. 109+/-4mg/dL), and presence of segmental + global glomerulosclerosis (20.1+/-3.2% vs. 0.1+/-0.1%) with prominent tubular and interstitial changes (p < 0.05, OB vs. LN, respectively). In summary, the present study indicates that the crossing of rat strains of nephropathy produces hybrids that carry a high risk for severe renal dysfunction. The ZDFxSHHF rats express insulin resistance, hypertension, dislipidemia and obesity and develop severe renal dysfunction. In addition, the hybrids do not develop some of the complications (hydronephrosis or congestive heart failure) common for the parental strains that may compromise studies of renal function and structure. Therefore, the ZDFxSHHF rat may be a useful model fore valuating risk factors and pharmacological interventions in chronic renal failure.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypertension  IAGP 401965414; 401965414; 401965414compared to WKY controlsRGD 
Metabolic Syndrome  ISOLepr (Rattus norvegicus)401965414; 401965414DNA:mutations::cds: : (rat)RGD 
Metabolic Syndrome  IAGP 401965414DNA:mutations::cds: : (rat)RGD 
Metabolic Syndrome MODEL: spontaneousIAGP 401965414compared ZSF1-Leprlean/Crl leptin receptor sufficient littermatesRGD 
Metabolic Syndrome MODEL: controlIAGP 401965414compared to ZSF1-Leprfa/cp/Crl (RS:0005316)RGD 
obesity  ISOLepr (Rattus norvegicus)401965414; 401965414DNA:mutations::cds: : (rat)RGD 
obesity  IAGP 401965414DNA:mutations::cds: : (rat)RGD 
obesity MODEL: spontaneousIAGP 401965414compared ZSF1-Leprlean/Crl leptin receptor sufficient littermatesRGD 
obesity MODEL: controlIAGP 401965414compared to ZSF1-Leprfa/cp/Crl (RS:0005316)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal cardiac muscle contractility  IAGP 401965414; 401965414; 401965414compared to WKY controlsRGD 
arteriosclerosis  IAGP 401965414DNA:mutations:cds: : ratRGD 
arteriosclerosis  IAGP 401965414compared to WKY and SHRRGD 
arteriosclerosis  IAGP 401965414compared to WKY more ...RGD 
decreased creatinine clearance  IAGP 401965414DNA:mutations:cds: : ratRGD 
decreased creatinine clearance  IAGP 401965414compared to WKY and SHRRGD 
decreased creatinine clearance  IAGP 401965414compared to WKY more ...RGD 
decreased left ventricle diastolic pressure  IAGP 401965414; 401965414compared to SHR controlsRGD 
decreased renal glomerular filtration rate  IAGP 401965414DNA:mutations::cds: : ratRGD 
decreased renal glomerular filtration rate  IAGP 401965414compared to lean littermates ZSF1-Leprlean/Crl RS:0005317RGD 
decreased renal plasma flow rate  IAGP 401965414DNA:mutations::cds: : ratRGD 
decreased renal plasma flow rate  IAGP 401965414compared to lean littermates ZSF1-Leprlean/Crl RS:0005317RGD 
dilated renal tubule  IAGP 401965414DNA:mutations:cds: : ratRGD 
dilated renal tubule  IAGP 401965414compared to WKY and SHRRGD 
dilated renal tubule  IAGP 401965414compared to WKY more ...RGD 
glomerulosclerosis  IAGP 401965414compared to WKY and SHRRGD 
glomerulosclerosis  IAGP 401965414compared to WKY more ...RGD 
increased body weight  IAGP 401965414DNA:mutations::cds: : ratRGD 
increased body weight  IAGP 401965414compared to lean littermates ZSF1-Leprlean/Crl RS:0005317RGD 
increased circulating cholesterol level  IAGP 401965414DNA:mutations:cds: : ratRGD 
increased circulating cholesterol level  IAGP 401965414compared to WKY and SHRRGD 
increased circulating cholesterol level  IAGP 401965414compared to WKY more ...RGD 
increased circulating creatinine level  IAGP 401965414compared to WKY and SHRRGD 
increased circulating glucose level  IAGP 401965414DNA:mutations:cds: : ratRGD 
increased circulating glucose level  IAGP 401965414compared to WKY and SHRRGD 
increased circulating glucose level  IAGP 401965414compared to WKY more ...RGD 
increased circulating insulin level  IAGP 401965414compared to WKY more ...RGD 
increased fluid intake  IAGP 401965414DNA:mutations::cds: : ratRGD 
increased fluid intake  IAGP 401965414compared to lean littermates ZSF1-Leprlean/Crl RS:0005317RGD 
increased heart weight  IAGP 401965414; 401965414compared to SHR and WKY controlsRGD 
increased kidney weight  IAGP 401965414compared to WKY more ...RGD 
increased left ventricle diastolic pressure  IAGP 401965414compared to WKY and SHRRGD 
increased left ventricle systolic pressure  IAGP 401965414; 401965414; 401965414compared to WKY controlsRGD 
increased mean systemic arterial blood pressure  IAGP 401965414; 401965414; 401965414compared to WKY controlsRGD 
increased renal vascular resistance  IAGP 401965414DNA:mutations::cds: : ratRGD 
increased renal vascular resistance  IAGP 401965414compared to lean littermates ZSF1-Leprlean/Crl RS:0005317RGD 
increased triglyceride level  IAGP 401965414DNA:mutations:cds: : ratRGD 
increased triglyceride level  IAGP 401965414compared to WKY and SHRRGD 
increased triglyceride level  IAGP 401965414compared to WKY more ...RGD 
increased urine flow rate  IAGP 401965414DNA:mutations:cds: : ratRGD 
increased urine flow rate  IAGP 401965414compared to WKY and SHRRGD 
increased urine flow rate  IAGP 401965414compared to WKY more ...RGD 
increased urine protein level  IAGP 401965414DNA:mutations:cds: : ratRGD 
increased urine protein level  IAGP 401965414compared to WKY and SHRRGD 
increased urine protein level  IAGP 401965414compared to WKY more ...RGD 
renal cast  IAGP 401965414DNA:mutations:cds: : ratRGD 
renal cast  IAGP 401965414compared to WKY and SHRRGD 
renal cast  IAGP 401965414compared to WKY more ...RGD 
renal interstitial fibrosis  IAGP 401965414DNA:mutations:cds: : ratRGD 
renal interstitial fibrosis  IAGP 401965414compared to WKY and SHRRGD 
renal interstitial fibrosis  IAGP 401965414compared to WKY more ...RGD 
renal tubule atrophy  IAGP 401965414DNA:mutations:cds: : ratRGD 
renal tubule atrophy  IAGP 401965414compared to WKY and SHRRGD 
renal tubule atrophy  IAGP 401965414compared to WKY more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Lepr  (leptin receptor)

Genes (Mus musculus)
Lepr  (leptin receptor)

Genes (Homo sapiens)
LEPR  (leptin receptor)

Strains
SHHF  (NA)
SHR  (Spontaneously Hypertensive Rat)
ZSF1-Leprfa/cp/Crl  (NA)
ZSF1-Leprlean/Crl  (NA)


Additional Information