Over 400,000 Americans have end-stage renal disease (ESRD) requiring dialysis or kidney transplant for survival. ESRD in the US population doubled in the last decade and this increase is driven by diabetes and hypertension. ESRD is associated with very high rates of mortality, most frequently from cardiovascular disease (CVD), and the heightened risk of CVD in individuals with chronic renal injury means that they are much more likely to die of CVD than to progress to ESRD. There is great variation in risk for ESRD among individuals who have hypertension and/or diabetes. The major determinant of this variation in risk is genetic susceptibility that serves to enhance the capacity of hypertension and diabetes to generate renal injury. The proposed studies focus on an animal model of renal injury with concurrent hypertension, insulin resistance and dyslipidemia, the spontaneously hypertensive rat (SHR). This model recapitulates the role of genetic susceptibility to renal injury in hypertensive and diabetic patients: the SHR-A3 line acquires hypertensive renal injury, while other hypertensive SHR lines resist it. These contrasting SHR lines offer a valuable means to identify the mechanism of and the genes contributing to susceptibility to renal injury. The proposed studies are made possible by our recent progress in defining a set of high density, single nucleotide polymorphism (SNP) markers in our injury-prone (SHR-A3) and resistant (SHRB2) lines that allow high resolution genetic mapping of loci controlling susceptibility to renal injury. We propose here to use these markers to map an intercross of these parental lines that will identify injury susceptibility loci. The conclusions of our mapping study will be tested and verified by breeding reciprocal congenic strains that fix injury resistance and susceptibility alleles in the injury-prone SHR-A3 and the injury-resistant SHR-B2 lines. Finally, we have uncovered the role of renal redox stress in the generation of renal injury in SHR-A3 and identified a transcriptional program that leads to this redox stress. This provides an opportunity to refine our genetic mapping studies down to the level of specific genes within the mapped loci. Genes that are functionally correlated to the transcriptional pathway of renal redox stress that we have elucidated in SHR-A3 will be targeted for selective resequencing to identify specific gene variants that drive the renal injury pathway.

Public Health Relevance

Kidney injury caused by diabetes and high blood pressure requires that more than 400,000 Americans be treated by kidney dialysis in order to survive. Heredity plays a major role in risk of kidney injury. Among diabetic and high blood pressure patients, the largest risk of progressive kidney disease is the occurrence of this disease in a relative. In the proposed studies we will use a rat model of this syndrome to genetically map chromosomal regions harboring genes that create risk of kidney injury. By uncovering the genes that cause this injury in rats and how this injury is created by these genes we will open up valuable new opportunities to understand the disease in people and to envision and test new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK081866-01
Application #
7513392
Study Section
Special Emphasis Panel (ZRG1-RUS-C (02))
Program Officer
Rasooly, Rebekah S
Project Start
2009-09-25
Project End
2011-07-31
Budget Start
2009-09-25
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$349,979
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Genetics
Type
Schools of Public Health
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Kneedler, Sterling C; Phillips, Lauren E; Hudson, Kayla R et al. (2017) Renal inflammation and injury are associated with lymphangiogenesis in hypertension. Am J Physiol Renal Physiol 312:F861-F869
Dhande, Isha S; Zhu, Yaming; Braun, Michael C et al. (2017) Mycophenolate mofetil prevents cerebrovascular injury in stroke-prone spontaneously hypertensive rats. Physiol Genomics 49:132-140
Mamenko, Mykola; Dhande, Isha; Tomilin, Viktor et al. (2016) Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus. J Am Soc Nephrol 27:2035-48
Braun, Michael C; Herring, Stacy M; Gokul, Nisha et al. (2014) Hypertensive renal injury is associated with gene variation affecting immune signaling. Circ Cardiovasc Genet 7:903-10
Gonzalez-Garay, M L; Cranford, S M; Braun, M C et al. (2014) Diversity in the preimmune immunoglobulin repertoire of SHR lines susceptible and resistant to end-organ injury. Genes Immun 15:528-33
Braun, Michael C; Herring, Stacy M; Gokul, Nisha et al. (2013) Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines. J Hypertens 31:2050-9
Doris, Peter A (2012) Genetic susceptibility to hypertensive renal disease. Cell Mol Life Sci 69:3751-63
Braun, Michael C; Doris, Peter A (2012) Mendelian and trans-generational inheritance in hypertensive renal disease. Ann Med 44 Suppl 1:S65-73
Bell, Rebecca; Herring, Stacy M; Gokul, Nisha et al. (2011) High-resolution identity by descent mapping uncovers the genetic basis for blood pressure differences between spontaneously hypertensive rat lines. Circ Cardiovasc Genet 4:223-31
Doris, Peter A (2011) The genetics of blood pressure and hypertension: the role of rare variation. Cardiovasc Ther 29:37-45

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