Genetic Susceptibility to Hypertension-Induced Renal Injury
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See related article, pp 700–708
Diabetes mellitus and hypertension are the leading causes of chronic kidney disease (CKD) and end-stage renal disease, but little is known about the genes involved. The present study by Dhande et al1 validated 2 regions of the genome that together completely account for CKD in stroke-prone spontaneously hypertensive rats (SpSHR). This study is highly significant because 1 in 7 Americans have CKD, and the Medicaid costs for treatment of patients with end-stage renal disease and CKD are 34 and 64 billion dollars/yr, respectively.2 Most patients with mild or moderate hypertension do not develop proteinuria or significant renal injury, indicating that there are differences in the genetic susceptibility.3,4 Renoprotection is also seen in spontaneously hypertensive rats (SHR) and angiotensin-dependent rodent models of hypertension that is associated with an elevation in renal vascular resistance that prevents transmission of systemic pressure to the glomerular capillaries.3,4 However, renal autoregulation is often impaired in patients with diabetes mellitus and blacks with low renin forms of hypertension that exhibit increased susceptibility to proteinuria and glomerulosclerosis in response to even modest elevations in pressure.3,4 Thus, there is tremendous interest in defining the genes and pathways that influence the susceptibility to hypertension-induced renal injury. Whole genome-wide association studies have uncovered susceptibility loci on nearly every chromosome.5 However, progress in identifying the causal genes remains limited. To date, only variants in apolipoprotein 1 and cubulin have been found to elevate the risk of CKD in blacks and albuminuria in diabetic patients.5
Genetic mapping studies using strains of rats that are susceptible (fawn-hooded hypertensive, Dahl salt-sensitive, buffalo, Munich Wistar Furth, and SpSHR) and resistant (spontaneously hypertensive, Brown-Norway, Wistar Kyoto, Lewis, August Copenhagen …