A 4.1-Mb Congenic Region of Rf-4 Contributes to Glomerular Permeability

• Published in: Journal of the American Society of Nephrology Vol. 23; no. 5; pp. 825 - 833
• Main Authors: O'MEARA, Caitlin C, LUTZ, Michelle M, JACOB, Howard J, SARKIS, Allison B, HAIYAN XU, KOTHINTI, Rajendra K, HOFFMAN, Matthew, MORENO, Carol, TABATABAI, Niloofar M, LAZAR, Jozef, ROMANY, Richard J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.05.2012
• Subjects: Animals; Animals, Congenic; Basic Research; Biological and medical sciences; Blood Pressure; Chromosome Mapping; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Hypertension - genetics; Kidney Diseases - genetics; Kidney Glomerulus - metabolism; Medical sciences; Nephrology. Urinary tract diseases; Permeability; Phenotype; Proteinuria - genetics; Quantitative Trait Loci; Rats; Renal glomerulus; Nephrology; Urinary system; Congenic; Permeability; Kidney; Urology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2011080805

The combined transfer of two renal function quantitative trait loci (QTLs), Rf-1 (rat chromosome 1) and Rf-4 (rat chromosome 14), from the Fawn-hooded hypertensive rat onto the August Copenhagen Irish genetic background significantly increases proteinuria and demonstrates an interaction between these QTLs. Because the original Rf-4 congenic region is 61.9 Mbp, it is necessary to reduce this interval to feasibly search for variants responsible for renal susceptibility in this region. Here, we generated a minimal congenic line (Rf-1a+4_a) to identify a 4.1-Mb region of the Rf-4 QTL that significantly contributes to the severity of proteinuria in the Fawn-hooded hypertensive rat. Rf-1a+4_a animals have an increased glomerular permeability to albumin without significant changes in BP, indicating that at least one genetic element in this refined region directly affects renal function. Sequence analysis revealed no variants predicted to damage protein function, implying that regulatory elements are responsible for the Rf-4 phenotype. Multiple human studies, including recent genome-wide association studies, link the homologous human region with susceptibility to renal disease, suggesting that this congenic line is an important model for studying pathways that contribute to the progression of kidney disease.