Long term control of blood pressure involves Na+ homeostasis through the precise regulation of the Epithelial Na+ Channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). ENaC dysfunction is causative for disturbances in total body Na+ levels associated with abnormal regulation of blood volume, blood pressure, and lung fluid balance. We provide preliminary evidence that epidermal growth factor (EGF) can serve as an ENaC ligand and hypothesize that members of the EGF-family and Rac1 modulate ENaC-mediated Na+ transport in the ASDN and participate in the development of salt-sensitive hypertension. EGF and its related EGF-family members bind to ErbB receptors and act as signaling factors responsible for renal development, physiology and pathophysiology. Under physiological conditions, ErbB receptors play an important role in the regulation of renal hemodynamics and electrolyte handling by the kidney, while in different pathophysiological states ErbB activation may mediate either beneficial or detrimental effects on the kidney. Stimulation of ErbB receptors activates an intracellular cascade involving small GTPases, particularly Rac1. Small G proteins and their regulatory proteins contribute to the pathology of renal and cardiovascular diseases. Our preliminary results, including electrophysiological experiments using isolated, split open ASDN, demonstrate that ENaC is regulated by EGF and Rac1, possibly through a convergent mechanism. Dahl salt-sensitive (SS) rats used in these studies develop severe hypertension on high-salt diet. We provide preliminary data indicating that ENaC contributes to the development of hypertension in the SS rat strain. Furthermore, our preliminary data reveal that EGF concentration is reduced in the SS rats, which we propose would enhance ENaC activity, sodium retention and hypertension. Building upon this preliminary data and our previously published findings, the specific objective of this proposal is to determine whether EGF acting through Rac1 is important for physiologic control of renal sodium handling through regulation of ENaC and define the precise mechanisms of EGF- and Rac1-mediated changes in ENaC activity. A combination of electrophysiological, immunohistochemical, biochemical, microscopy and chronic studies in vivo and in vitro will be used in this proposal to provide mechanistic insights on how ENaC is regulated by member of the EGF-family and Rac1 and how changes in this pathway contributes to salt induced hypertension in SS rats. These studies will address three Specific Aims: 1) To identify and quantify the role of EGF and related growth factors in the physiological regulation of ENaC activity in the ASDN and establish the role of this pathway in the development of salt-sensitive hypertension;2) To establish the physiological role of RhoGDI and Rac1 in regulation of ENaC and determine the role of Rac1 in mediating EGF effects on ENaC;and 3) To define the cellular and molecular mechanism by which Rac1 modulates ENaC activity: do WAVEs convey Rac1 regulation to ENaC?

Public Health Relevance

The control of blood pressure occurs via Na+ homeostasis in the kidney and involves the precise regulation of the Epithelial Na+ Channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). The current proposal will study how members of the epidermal growth factors family and small GTPase Rac1 modulate ENaC- mediated Na+ transport in the ASDN and participate in the development of salt-sensitive hypertension. This work has the potential to provide new insights into the control and function of this important ion channel and uncover mechanisms involved in diseases associated with fluid imbalance and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108880-02
Application #
8389894
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (04))
Program Officer
Maric-Bilkan, Christine
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$364,140
Indirect Cost
$126,140
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Palygin, O; Pochynyuk, O; Staruschenko, A (2017) Role and mechanisms of regulation of the basolateral Kir 4.1/Kir 5.1K+ channels in the distal tubules. Acta Physiol (Oxf) 219:260-273
Ilatovskaya, Daria V; Palygin, Oleg; Levchenko, Vladislav et al. (2017) The Role of Angiotensin II in Glomerular Volume Dynamics and Podocyte Calcium Handling. Sci Rep 7:299
Pavlov, Tengis S; Levchenko, Vladislav; Ilatovskaya, Daria V et al. (2017) Lack of Effects of Metformin and AICAR Chronic Infusion on the Development of Hypertension in Dahl Salt-Sensitive Rats. Front Physiol 8:227
Pavlov, Tengis S; Staruschenko, Alexander (2017) Involvement of ENaC in the development of salt-sensitive hypertension. Am J Physiol Renal Physiol 313:F135-F140
Palygin, Oleg; Levchenko, Vladislav; Ilatovskaya, Daria V et al. (2017) Essential role of Kir5.1 channels in renal salt handling and blood pressure control. JCI Insight 2:
Palygin, Oleg; Ilatovskaya, Daria V; Staruschenko, Alexander (2016) Protease-activated receptors in kidney disease progression. Am J Physiol Renal Physiol 311:F1140-F1144
Staruschenko, Alexander; Ilatovskaya, Daria V; Pavlov, Tengis S (2016) High salt diet and caffeine: food for thought. J Thorac Dis 8:E1410-E1412
Zappia, Katherine J; Garrison, Sheldon R; Palygin, Oleg et al. (2016) Mechanosensory and ATP Release Deficits following Keratin14-Cre-Mediated TRPA1 Deletion Despite Absence of TRPA1 in Murine Keratinocytes. PLoS One 11:e0151602
Ilatovskaya, Daria V; Palygin, Oleg; Staruschenko, Alexander (2016) Functional and therapeutic importance of purinergic signaling in polycystic kidney disease. Am J Physiol Renal Physiol 311:F1135-F1139
Blass, Gregory; Levchenko, Vladislav; Ilatovskaya, Daria V et al. (2016) Chronic cathepsin inhibition by E-64 in Dahl salt-sensitive rats. Physiol Rep 4:

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