In the prior funding period we have introduced a new approach to genetic mapping in inbred rodent strains that exploits closely related lines differing in traits of interest. Using a 10K SNP map, we have shown that two SHR lines differ at only 13% of their genomes, but that these differences have a profound effect on susceptibility to hypertensive renal disease. The close genetic similarity has allowed us to perform fine mapping that has resulted in the identification of three highly resolved quantitative trait loci (QTL) affecting blood pressure and renal injury. Because of the similarity between the lines, each of these QTL maps to a small, isolated block where the two SHR lines have descended from different ancestors. These blocks are surrounded by extensive regions that are identical-by-descent (IBD) and thus help to narrowly define the QTL's, down to a small number of genes. In the present study we propose to identify the genes in each QTL that contribute to increased hypertensive renal disease and to understand the mechanisms by which they act. One QTL has effects on both blood pressure and renal injury. We seek to identify the causative variation and determine whether it acts first on blood pressure with secondary effects on injury or whether it lies in a pathway that produces injury that then leads to reduced renal function and increased blood pressure. Another QTL has no effect on blood pressure and appears to lead to glomerular damage directly. We have also identified the immunoglobulin heavy chain as a locus containing extensive variation across our lines. We have shown that this includes variation with important effects on IgG function including the inability to transfer IgG from mother to offspring. This variation associates with increased albuminuria. We propose to investigate whether alterations in immune function that are encoded by differences in the heavy chain of immunoglobulin contribute to the emergence of renal disease in the susceptible SHR line and whether maternal-offspring IgG transfer is involved in the transmission of risk. We have identified allelic variatio in IgG in humans that is widespread and ancient and that is functionally homologous to the variation we detected across SHR lines. We will perform a large-scale human population genetic study to determine the association of this variation with renal function in humans.
Each year over 400,000 Americans reach the point at which their kidney function is no longer sufficient to support life. Dialysis or transplantation are necessary, however, even with these therapies life expectancy is dramatically reduced. While high blood pressure and diabetes are the two major factors acting to enhance risk of renal failure within populations, at the individual level risk is most greatly affected by genetic factor. This means that the presence of a relative who has reached end stage renal function is the most powerful predictor of an individual risk's risk of progressive renal disease. In the present studies we seek to understand how genetic factors increase risk that high blood pressure will cause loss of renal function. We use a rat model that greatly simplifies the genetics and allows aspects of renal injury (measured by histological examination of the kidney tissue) to be assessed that cannot be examined in human populations. Our work implicates elements of immune function in renal injury. An important element is our proposal that chromosomal DNA is not the only means by which heritable risk of renal injury is transmitted and that transmission via IgG passed from mothers to progeny also contributes to heritability of risk.
|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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