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Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines

Braun, Michael C.c; Herring, Stacy M.a; Gokul, Nishaa; Monita, Moniquea; Bell, Rebeccaa; Hicks, M. Johnb; Wenderfer, Scott E.c; Doris, Peter A.a

doi: 10.1097/HJH.0b013e328362f9a5
ORIGINAL PAPERS: Kidney

Background: Spontaneously hypertensive rat (SHR) lines differ in their susceptibility to hypertensive end-organ disease and may provide an informative model of genetic risk of disease. Lines derived from the original SHR-B and SHR-C clades are highly resistant to hypertensive end-organ disease, whereas lines derived from the SHR-A clade were selected for stroke susceptibility and experience hypertensive renal disease.

Method: Here we characterize the temporal development of progressive renal injury in SHR-A3 animals consuming 0.3% sodium in the diet and drinking water. SHR-A3 rats demonstrate albuminuria, glomerular damage, tubulointerstitial injury, and renal fibrosis that emerge at 18 weeks of age and progress.

Results and conclusion: Mortality of SHR-A3 animals was 50% at 40 weeks of age, and animals surviving to this age had reduced renal function. In contrast SHR-B2, which are 87% genetically identical to SHR-A3, are substantially protected from renal injury and demonstrate only moderate changes in albuminuria and renal histological injury over this time period. At 40 weeks of age, electron microscopy of the renal glomerulus revealed severe podocyte effacement in SHR-A3, but slit diaphragm architecture in SHR-B2 at this age was well preserved. Renal injury traits in the F1 and F2 progeny of an intercross between SHR-A3 and SHR-B2 were measured to determine heritability of renal injury in this model. Heritability of albuminuria, glomerular injury, and tubulointerstitial injury were estimated at 48.9, 66.5 and 58.6%, respectively. We assessed the relationship between blood pressure and renal injury measures in the F2 animals and found some correlation between these variables that explain up to 26% of the trait variation. Quantitative trait locus (QTL) mapping was performed using over 200 single nucleotide polymorphism markers distributed across the 13% of the genome that differs between these two closely related lines. Mapping of albuminuria, tubulointerstitial injury, and renal fibrosis failed to identify loci linked with disease susceptibility, suggesting a complex inheritance of disease risk. We detected a single QTL conferring susceptibility to glomerular injury that was confined to a small haplotype block at chromosome 14:70–76Mb.

aInstitute of Molecular Medicine, University of Texas HSC at Houston

bDepartment of Pathology and Immunology

cDepartment of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA

Correspondence to Peter A. Doris, PhD, Institute of Molecular Medicine, University of Texas HSC at Houston, 1825 Pressler Street, Suite 530F, Houston, TX 77030, USA. Tel: +1 713 500 2414; fax: +1 713 500 2447; e-mail: peter.a.doris@uth.tmc.edu

Abbreviations: AAALAC, American Association for the Advancement of Laboratory Animal Care; F1, first filial generation; F2, second filial generation; GWAS, genome-wide association study; IBD, identical by descent; PAS, Periodic acid Schiff's stain; QTL, quantitative trait locus; SHR, spontaneously hypertensive rat; SNP, single nucleotide polymorphism; uACR, urinary albumin:creatinine ratio

Received 6 November, 2012

Revised 8 April, 2013

Accepted 6 May, 2013

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins