There is an alarming increase in the incidence of end-stage renal disease in the Unites States, with hypertension and diabetes being the major cause. Currently, 25.6 million people are in the early phase of kidney disease (stage 1 to 3) and while strict control of blood pressure and glucose levels may slow, it will not prevent the progressive decline of renal function in these patients. Therefore, understanding the genetic basis of hypertension-induced renal disease is of considerable interest. Significant progress has been made to identify the genetic causes of familial forms of renal disease (nephrotic syndrome). However, no genetic variants have been found to be causally linked to common forms of renal disease. It is our goal to develop a better understanding of the genetic basis of hypertension-induced renal disease observed in the Dahl salt- sensitive (S) rat, which exhibits significant proteinuria and focal segmental glomerulosclerosis (FSGS). An initial genetic analysis for proteinuria and renal injury was performed using a population derived from the S. The study identified ten genomic regions linked to renal damage (measured by proteinuria) and/or function. A congenic strain developed on chromosome 2 exhibited significantly less proteinuria and FSGS. This proposal will evaluate the hypothesis that genetic variant(s) located to a small region on rat chromosome 2 play a significant role in the progressive FSGS and proteinuria observed in the S rat. Based on congenic strain analysis, the causative locus has been narrowed to <1.2 Mbs containing 27 genes. However, cross-species comparative, inbred-based SNP analysis, comprehensive coding sequence and gene expression analysis has convincingly identified 4 genes for further study.
The aims of the proposed study are: (1) to perform temporal studies of blood pressure and renal hemodynamics, including renal blood flow, glomerular capillary pressure, and glomerular permeability in the S and small congenic strain;(2) to perform comprehensive gene expression, western blot analysis, sequencing, and haplotype analysis for genes narrowed to the small region on rat chromosome 2;and (3) to evaluate the functional significance of identified allelic variants using cell- based and whole-animal approaches. In summary, this proposal will identify and prioritize gene(s) linked to proteinuria and FSGS in the Dahl S model of hypertension-induced renal disease and provide a basis for functional studies, gene validation, and eventually study in human-based populations.

Public Health Relevance

High blood pressure is major contributor to end-stage renal disease (ESRD). The number of ESRD patients treated by either dialysis or transplantation has more than doubled in the period from 1991 to 2004 from 209,000 to 472,000. In the next 20 years, the numbers of ESRD patients are expected to increase to over 2 million. Additionally, the economic impact is substantial, burdening the Medicare system (costing $20.1 billion or 7% percent of total Medicare expenditures), and the private insurance sector (estimated at $12.1 billion). The unfortunate reality is that treatment options are limited and only slow the progression of the disease. The focus of the proposed work is to identify genes that predispose the Dahl salt-sensitive (S) rat to develop hypertension-induced kidney disease. Previous genetic analysis using the S rat identified several chromosomal regions linked to kidney disease. In particular, a region on rat chromosome 2 was found to play a significant role in the kidney injury observed in the S rat. The homologous region on human chromosome 1q21 has also been linked to kidney disease in multiple studies. This underlies the importance in identifying the gene in the rat because the findings may be readily applied to human kidney disease. In summary, it is the goal of this proposal to utilize a rodent model of human disease and advanced genetic techniques to expedite the identification of a gene involved in kidney disease. The application of knowledge gained from this research will contribute to a better understanding of the how and why of the disease and ultimately provide earlier and more effective treatments of the disease before kidney failure is reached.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094446-05
Application #
8477235
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$352,252
Indirect Cost
$116,632
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Westbrook, Lindsey; Johnson, Ashley C; Regner, Kevin R et al. (2014) Genetic susceptibility and loss of Nr4a1 enhances macrophage-mediated renal injury in CKD. J Am Soc Nephrol 25:2499-510
Johnson, Ashley C; Lee, Jonathan W; Harmon, Ashlyn C et al. (2013) A mutation in the start codon of ýý-crystallin D leads to nuclear cataracts in the Dahl SS/Jr-Ctr strain. Mamm Genome 24:95-104
Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio et al. (2013) Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154:691-703
Pillai, Resmi; Waghulde, Harshal; Nie, Ying et al. (2013) Isolation and high-throughput sequencing of two closely linked epistatic hypertension susceptibility loci with a panel of bicongenic strains. Physiol Genomics 45:729-36
Slaughter, Tiffani N; Paige, Adrienne; Spires, Denisha et al. (2013) Characterization of the development of renal injury in Type-1 diabetic Dahl salt-sensitive rats. Am J Physiol Regul Integr Comp Physiol 305:R727-34
Regner, Kevin R; Harmon, Ashlyn C; Williams, Jan M et al. (2012) Increased susceptibility to kidney injury by transfer of genomic segment from SHR onto Dahl S genetic background. Physiol Genomics 44:629-37
Wiessner, John H; Garrett, Michael R; Hung, Linda Y et al. (2011) Improved methodology to induce hyperoxaluria without treatment using hydroxyproline. Urol Res 39:373-7
Solberg Woods, Leah C; Stelloh, Cary; Regner, Kevin R et al. (2010) Heterogeneous stock rats: a new model to study the genetics of renal phenotypes. Am J Physiol Renal Physiol 298:F1484-91
Garrett, Michael R; Pezzolesi, Marcus G; Korstanje, Ron (2010) Integrating human and rodent data to identify the genetic factors involved in chronic kidney disease. J Am Soc Nephrol 21:398-405