Ion channels are well recognized as important therapeutic targets because they play a crucial role in controlling a very wide spectrum of physiological processes. Human genetic studies identified a number of mutations in the renal ion channels leading to renal pathophysiology and abnormal changes in blood pressure. Understanding the basic mechanisms of ion channel regulation in the kidney and how alterations of such regulatory networks lead to water and electrolyte imbalance is fundamentally important for understanding of the development of hypertension and designing new strategies for treating this devastating and costly disease. The PI's research group has made key contributions in revealing specific mechanisms controlling several ion channels in the kidney and their contribution to the development of hypertension. Given the strong historical precedent that exists for discovering and commercializing successful drugs that modulate the activity of sodium, calcium, or potassium channels, and considering the critical role of renal ion channels in the control of blood pressure, new generations of therapeutic agents are expected to result from targeting ion channels in the kidney. The central tenet of this proposal is that several types of transporters, specifically ENaC, Kcnj10/Kcn16, Trpc6, and Clcn6, work either individually or in complex, interdependent combinations to delicately modulate the pressure natriuresis relationship and control blood pressure, respectively. The channels listed above were selected because either human mutations were reported in genes encoding these channels, or they were identified by Genome Wide Association Studies as genes associated with blood pressure control. Genomic modulation of channels and their regulators will be performed in the Dahl Salt- Sensitive (SS) rat, a well characterized and established model, which shares many features with salt-sensitive hypertension in humans. SS rat has been an enormously useful model as it is naturally occurring and recapitulates the major phenotypes found in hypertensive African Americans. Importantly, the SS model has been amenable to robust, cutting-edge genetic approaches to successfully create multiple mutant models, which will be used in this study. Considering the availability of these unique genetic rat models and novel approaches developed in my laboratory, I will be able to systematically study critical changes in corresponding ion transport mechanisms and downstream signaling pathways in the setting of salt-induced hypertension. The overall goal of this R35 proposal is to understand the impact of specific human gene variations on ion channel function and contribute to our understanding of the role of renal ion channels in normal and pathophysiological control of blood pressure.

Public Health Relevance

Nearly 78 million American adults have hypertension, which is one of the major risk factors for stroke, coronary heart disease and renal failure. Salt and water handling by the kidney directly impact blood pressure, whereas ion channels maintain electrolyte homeostasis. I propose here to study the concerted contributions of several renal ion channels with known links to human disease in a rat model that closely resembles many features of salt-sensitive hypertension in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
1R35HL135749-01
Application #
9242307
Study Section
Special Emphasis Panel (ZHL1-CSR-I (O2))
Program Officer
OH, Youngsuk
Project Start
2017-01-15
Project End
2023-12-31
Budget Start
2017-01-15
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$385,000
Indirect Cost
$135,000
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Wright, Kevin D; Staruschenko, Alexander; Sorokin, Andrey (2018) Role of adaptor protein p66Shc in renal pathologies. Am J Physiol Renal Physiol 314:F143-F153
Shuyskiy, L S; Levchenko, V V; Negulyaev, Y A et al. (2018) Role of the Scaffold Protein MIM in the Actin-Dependent Regulation of Epithelial Sodium Channels (ENaC). Acta Naturae 10:97-103
Spires, Denisha; Ilatovskaya, Daria V; Levchenko, Vladislav et al. (2018) Protective role of Trpc6 knockout in the progression of diabetic kidney disease. Am J Physiol Renal Physiol 315:F1091-F1097
Ho, Pei-Yin; Li, Hui; Pavlov, Tengis S et al. (2018) ?1Pix exchange factor stabilizes the ubiquitin ligase Nedd4-2 and plays a critical role in ENaC regulation by AMPK in kidney epithelial cells. J Biol Chem 293:11612-11624
Miller, Bradley S; Blumenthal, Shoshana R; Shalygin, Alexey et al. (2018) Inactivation of p66Shc Decreases Afferent Arteriolar KATP Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats. Diabetes 67:2206-2212
Parnell, Stephen C; Magenheimer, Brenda S; Maser, Robin L et al. (2018) A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD. Hum Mol Genet 27:3313-3324
Palygin, Oleg; Ilatovskaya, Daria V; Levchenko, Vladislav et al. (2018) Nitric oxide production by glomerular podocytes. Nitric Oxide 72:24-31
Palygin, Oleg; Miller, Bradley S; Nishijima, Yoshinori et al. (2018) Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion. FASEB J :fj201800776RR
Staruschenko, Alexander (2018) Beneficial Effects of High Potassium: Contribution of Renal Basolateral K+ Channels. Hypertension 71:1015-1022
Palygin, Oleg; Ilatovskaya, Daria V; Levchenko, Vladislav et al. (2018) Characterization of purinergic receptor expression in ARPKD cystic epithelia. Purinergic Signal 14:485-497

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