Recent studies emphasize the importance of renal inflammation in causing defective sodium handling by the kidneys, a central feature of salt-sensitive hypertension. Yet, the precise mechanisms by which renal inflammation leads to renal sodium retention are not fully understood. We recently published that the activity of the angiotensin-converting enzyme (ACE) in renal tissues is indispensable for the development of experimental hypertension. Specifically, mice lacking renal ACE are resistant to traditional models of hypertension due to impaired local (renal) Ang II generation. Renal Ang II appears critical to the activity of several key sodium transporters, including the thick ascending limb Na+/K+/2Cl- transporter (NKCC2) and the distal tubule NaCl co- transporter (NCC);increased local Ang II synthesis by renal ACE results in sodium and water retention and hypertension. Based on these findings, this proposal will address the hypothesis that the renal ACE/Ang II pathway is a master switch of sodium transport along the nephron, and inappropriate activation of this switch by inflammation or other renal injury triggers the renal sodium dysregulation that ultimately causes salt- sensitive hypertension. We conducted preliminary studies using the post-L NAME hypertension model. In this, the transient exposure to L-NAME (4 weeks) is followed by a recovery phase (1 week) and finally exposure to a high salt diet (3 weeks). The initial insult (L NAME) induces renal inflammation and leads to salt-sensitivity and hypertension in previously normal (i.e. salt resistant) mice. We now present evidence that mice lacking ACE in renal tissues do NOT develop post L-NAME salt-sensitivity. Further, mice lacking renal ACE maintain a normal renal response to high salt despite substantial levels of renal inflammation induced by the protocol.
Two aims are proposed to further investigate these very novel observations:
Aim 1 is to determine the quantitative contribution of tubular epithelial ACE to salt-sensitive hypertension. Our hypothesis is that ACE from the epithelial cells of the nephron is the major source of local Ang II in response to the parenchymal inflammation inducing salt-sensitivity. To do this, we created a transgenic model in which tubular ACE expression can be turned on/off;we will investigate the responses of these mice to the post-L NAME model.
Aim 2 is to study the in vivo biochemical basis of the renal ACE/Ang II master switch. Our hypothesis is that local Ang II synthesis by renal ACE increases NCC abundance, NKCC2 and NCC phosphorylation (via the kinase SPAK) and cell surface expression of NKCC2 and NCC. To test this, we will determine the regulation of NKCC2 and NCC in wild-type and mice lacking renal ACE during post-L NAME hypertension. By studying this very novel and obligatory interaction between renal injury and the master switch of renal ACE, our studies will provide novel and mechanistic insights into the origins of salt-sensitive hypertension, a condition affecting 1 in every 2 hypertensive patients.

Public Health Relevance

Our preliminary studies suggest that the activity of the angiotensin-converting enzyme (ACE) in renal tissue, and its product angiotensin II, play an indispensable role in the sodium retention and the hypertension occurring in response to renal inflammation/injury. Our goal is to study this pathway to yield ways to prevent and to treat the sodium retentive state of many individuals affected by hypertension and renal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK101592-01
Application #
8677333
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Mcbryde, Kevin D
Project Start
2014-09-01
Project End
2017-06-30
Budget Start
2014-09-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Eriguchi, Masahiro; Lin, Mercury; Yamashita, Michifumi et al. (2018) Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy. Am J Physiol Renal Physiol 314:F531-F542
Eriguchi, Masahiro; Bernstein, Ellen A; Veiras, Luciana C et al. (2018) The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease. J Am Soc Nephrol 29:2546-2561
Bernstein, Kenneth E; Khan, Zakir; Giani, Jorge F et al. (2018) Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol 14:325-336
Khan, Zakir; Shen, Xiao Z; Bernstein, Ellen A et al. (2017) Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood 130:328-339
Giani, Jorge F; Eriguchi, Masahiro; Bernstein, Ellen A et al. (2017) Renal tubular angiotensin converting enzyme isĀ responsible for nitro-L-arginine methyl esterĀ (L-NAME)-induced salt sensitivity. Kidney Int 91:856-867
Giani, Jorge F; Shah, Kandarp H; Khan, Zakir et al. (2015) The intrarenal generation of angiotensin II is required for experimental hypertension. Curr Opin Pharmacol 21:73-81
Giani, Jorge F; Bernstein, Kenneth E; Janjulia, Tea et al. (2015) Salt Sensitivity in Response to Renal Injury Requires Renal Angiotensin-Converting Enzyme. Hypertension 66:534-42
Giani, Jorge F; Janjulia, Tea; Taylor, Brian et al. (2014) Renal generation of angiotensin II and the pathogenesis of hypertension. Curr Hypertens Rep 16:477
Giani, Jorge F; Janjulia, Tea; Kamat, Nikhil et al. (2014) Renal angiotensin-converting enzyme is essential for the hypertension induced by nitric oxide synthesis inhibition. J Am Soc Nephrol 25:2752-63