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.
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.