Diabetes and hypertension are the leading causes of chronic kidney disease (CKD) and the incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and elevations in glomerular capillary pressure that promote the development of renal injury. However, only half of patients with diabetes or hypertension develop renal disease and very little is known about the susceptibility genes. For many years our group has been studying the Fawn-Hooded Hypertensive (FHH) rat which is a genetic model of hypertension-induced CKD that develops progressive proteinuria and glomerulosclerosis. We have reported that FHH rats exhibit an impaired myogenic response and autoregulation of blood flow in both the renal and cerebral circulations. However, the genes and pathways involved are unknown. This proposal builds upon our exciting preliminary results indicating that the myogenic response of the afferent arteriole and autoregulation of RBF is impaired in FHH rats due to an elevation in the activity of the large conductance, calcium-activated potassium (BK) channel and that substitution of a region of chromosome 1 containing just 15 genes from the Brown Norway rat onto the FHH genetic background normalizes BK channel activity, restores the myogenic response and autoregulation of RBF and attenuates the development of renal disease. Sequencing and expression analysis of the genes in this region identified a sequence variant in adducin 3 (Add3) that is predicted to damage protein function. The goal of this project is to use molecular and transgenic approaches to explore the role of Add3 in mediating the impaired myogenic response in FHH rats, to study the cellular and ionic mechanisms involved and the functional consequences of impaired autoregulation of RBF to the development of renal damage following the development of hypertension or diabetes. Add3 was chosen for study since Milan Normotensive rats share the same K572Q mutation in Add3 as FHH rats and they are also highly susceptible to the development of renal disease. In addition, mutations in the Add gene family have been repeatedly linked to the development of hypertension and vascular dysfunction in human association studies. The role of Add3 will be evaluated using complementary approaches including: siRNA knockdown of Add3 in renal arterioles, novel Add3 transgenic rescue FHH rats and Zn-finger nuclease Add3 knockout (KO) strains of rats that we created. We will characterize the myogenic response in isolated afferent arterioles and measure BK channel activity in vascular smooth muscle cells isolated from FHH rats and the Add3 KO and transgenic strains. The proposed studies will reveal how Add3 and its associated downstream pathways regulate BK channel activity and the myogenic response, and will provide information critical to the development of new treatments for the prevention of CKD in diabetic and hypertensive patients in which renal autoregulation is often impaired.

Public Health Relevance

Impaired autoregulation of renal blood flow with increased transmission of pressure to the renal microcirculation is a common feature in the development of renal disease in hypertensive and diabetic patients but the genes and pathways involved are unknown. This proposal will study the genetic basis of renal disease in Fawn Hooded rats that have abnormal renal hemodynamics and develop proteinuria and renal injury. These studies are based on our recent discovery that transfer of a small segment of Chromosome 1 containing just 15 genes from the BN rat into the FHH genetic background restores autoregulation of renal blood flow and attenuates the development of renal disease. This proposal will test the hypothesis that a mutation in the Add3 gene is responsible for the development of hypertension induced renal damage in FHH rats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104184-04
Application #
9317288
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ketchum, Christian J
Project Start
2014-09-25
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Ge, Ying; Fan, Fan; Didion, Sean P et al. (2017) Impaired myogenic response of the afferent arteriole contributes to the increased susceptibility to renal disease in Milan normotensive rats. Physiol Rep 5:
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