RGD Reference Report - Unmasking of proteinuria in the course of genetic dissection of nonproteinuric diabetic nephropathy. - Rat Genome Database

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Unmasking of proteinuria in the course of genetic dissection of nonproteinuric diabetic nephropathy.

Authors: Yagil, Y  Roif, D  Sapojnikov, M  Ben-Dor, D  Tobar, A  Rosenmann, E  Yagil, C 
Citation: Yagil Y, etal., Physiol Genomics. 2014 Jan 1;46(1):29-38. doi: 10.1152/physiolgenomics.00133.2013. Epub 2013 Nov 5.
RGD ID: 8552897
Pubmed: PMID:24192394   (View Abstract at PubMed)
DOI: DOI:10.1152/physiolgenomics.00133.2013   (Journal Full-text)

We previously described the development of nonproteinuric diabetic nephropathy (NPDN) in the Cohen diabetic rat (CDs), a model that simulates Type 2 diabetes in humans. Using linkage analysis in an F2 cross, we currently set out to investigate the mechanisms underlying NPDN. We crossbred between CDs and SBN/y, a nondiabetic rat strain, generated F1 and F2 progenies, fed them diabetogenic diet that elicits diabetes and NPDN in CDs but not in SBN/y, and determined metabolic and renal phenotypes. Over 5 mo, approximately 75% of F2 developed a diabetic phenotype. In parallel, a nephropathy developed in F2, with glomerular filtration rate (GFR) declining in approximately 25% and, unexpectedly, significant proteinuria appearing in approximately 75%. We scanned the F2 genome with microsatellite markers and used linkage analysis to identify quantitative trait loci (QTLs). We detected diabetes-related QTLs on RNO4 and 13. We also detected two QTLs for the decline in GFR on RNO4 and 13 and another QTL for proteinuria on RNO13. The metabolic and renal-related QTLs overlapped. These results suggest that the mechanisms underlying the nephropathy in F2 are related to genes that map to RNO4 and 13, as well as a common genetic background for the development of diabetes and the renal disease. Our findings further indicate that proteinuria is inhibited in parental diabetic CDs, thus accounting for the nonproteinuric phenotype, but "unmasked" in diabetic F2 whose genome has been modified. Identifying the nature of the factor inhibiting proteinuria in diabetic CDs but not in F2 may provide a clue to treatment and prevention of proteinuria in diabetes.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CDS/YglRatdiabetes mellitus MODEL: inducedIAGPcontrolled content dietcompared to SBN/YglRGD 
SBN/YglRatdiabetes mellitus MODEL: controlIAGPcontrolled content dietcompared to CDS/YglRGD 
CDS/YglRatDiabetic Nephropathies  IAGP  RGD 
Kidm43RatDiabetic Nephropathies  IAGP  RGD 
Pur32RatDiabetic Nephropathies  IAGP  RGD 
Rf60RatDiabetic Nephropathies  IAGP  RGD 
Rf61RatDiabetic Nephropathies  IAGP  RGD 
Rf62RatDiabetic Nephropathies  IAGP  RGD 
Rf63RatDiabetic Nephropathies  IAGP  RGD 
CDS/YglRatExperimental Diabetes Mellitus severityIAGPcontrolled content dietsexual dimorphismRGD 
Pur32Ratproteinuria  IAGP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

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Objects Annotated

QTLs
Kidm43  (Kidney mass QTL 43)
Pur32  (Proteinuria QTL 32)
Rf60  (Renal function QTL 60)
Rf61  (Renal function QTL 61)
Rf62  (Renal function QTL 62)
Rf63  (Renal function QTL 63)

Strains
CDS/Ygl  (Cohen diabetic-sensitive rat)
SBN/Ygl  (Sabra hypertension resistant)

Objects referenced in this article
Strain CDR/Ygl null Rattus norvegicus

Additional Information