Tea Janjulia

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.

Myeloid Suppressor Cells Accumulate and Regulate Blood Pressure in Hypertension

RATIONALE Chronic inflammation is a major contributor to the progressive pathology of hypertension, and T-cell activation is required for the genesis of hypertension. However, the precise role of myeloid cells in this process is unclear. OBJECTIVE To characterize and understand the role of peripheral myeloid cells in the development of hypertension. METHODS AND RESULTS We examined myeloid cells in the periphery of hypertensive mice and found that increased numbers of CD11b(+)Gr1(+) myeloid cells in blood and the spleen are a characteristic of 3 murine models of experimental hypertension (angiotensin II, L-NG-nitroarginine methyl ester, and high salt). These cells express surface markers and transcription factors associated with immaturity and immunosuppression. Also, they produce hydrogen peroxide to suppress T-cell activation. These are characteristics of myeloid-derived suppressor cells (MDSCs). Depletion of hypertensive MDSCs increased blood pressure and renal inflammation. In contrast, adoptive transfer of wild-type MDSCs to hypertensive mice reduced blood pressure, whereas the transfer of nicotinamide adenine dinucleotide phosphate oxidase 2-deficient MDSCs did not. CONCLUSION The accumulation of MDSCs is a characteristic of experimental models of hypertension. MDSCs limit inflammation and the increase of blood pressure through the production of hydrogen peroxide.

Rediscovering ACE: Novel insights into the many roles of the angiotensin-converting enzyme

Angiotensin-converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation, and immunity.

Renal Generation of Angiotensin II and the Pathogenesis of Hypertension

The existence of a complete and functional renin-angiotensin system along the nephron is widely recognized. However, its precise role in blood pressure control and, by extension, hypertension is still uncertain. While most investigators agree that overexpressing RAS components along the nephron results in hypertension, two important issues remain: whether the local RAS works as a separate entity or represents an extension of the systemic RAS and whether locally generated angiotensin II has specific renal effects on blood pressure that are distinct from systemic angiotensin II. This review addresses these issues while emphasizing the unique role of local angiotensin II in the response of the kidney to hypertensive stimuli and the induction of hypertension.

Nontraditional Roles of Angiotensin-Converting Enzyme

Many articles have described the biochemistry of the renin-angiotensin system (RAS). Simply put, renin and angiotensin-converting enzyme (ACE) produce angiotensin II, which affects the brain (increased thirst), the gut (increased salt absorption), the adrenals (aldosterone production), the kidneys (salt and water retention), the heart (increased cardiac output), and vascular smooth muscle (vasoconstriction). Inhibitors of ACE and the angiotensin II type 1 receptor are now widely used to reduce blood pressure and to treat hypertension, heart failure, and renal disease.1 The effectiveness of these drugs and abundant data from animal models show that the RAS is the bodys central mechanism for regulating blood pressure. Modern studies of the RAS have substantially broadened the known roles of this system by showing that angiotensin II influences cellular proliferation and the inflammatory response. Although this wider interpretation of the RAS encompasses more than control of blood pressure, it still focuses on the effects of angiotensin II in the context of vascular injury. This increased understanding of the RAS inevitably leads to the question of whether, even now, we fully understand all of the physiological roles of the RAS. Here, we argue that the answer is no, that nature uses the components of the RAS and, in particular, ACE for a wide variety of physiological tasks. ### ACE Is Necessary for Renal Development and Normal Male Fertility In understanding the function of the RAS, a powerful tool is the ability to genetically alter mouse genes. Knockout studies of angiotensinogen, renin, ACE, or the angiotensin II type 1 receptor have confirmed the important role of these proteins in regulating blood pressure, but they also underline the wider physiological role for the RAS.2 For example, adult mice lacking ACE show marked abnormalities of renal development characterized by hypertrophy of small arteries, interstitial fibrosis, atrophy of the inner medulla and renal papilla, and dilation of calyces. Renal …

Salt Sensitivity in Response to Renal Injury Requires Renal Angiotensin-Converting Enzyme

Recent evidence indicates that salt-sensitive hypertension can result from a subclinical injury that impairs the kidneys’ capacity to properly respond to a high-salt diet. However, how this occurs is not well understood. Here, we showed that although previously salt-resistant wild-type mice became salt sensitive after the induction of renal injury with the nitric oxide synthase inhibitor N&ohgr;-nitro-L-arginine methyl ester hydrochloride; mice lacking renal angiotensin-converting enzyme, exposed to the same insult, did not become hypertensive when faced with a sodium load. This is because the activity of renal angiotensin-converting enzyme plays a critical role in (1) augmenting the local pool of angiotensin II and (2) the establishment of the antinatriuretic state via modulation of glomerular filtration rate and sodium tubular transport. Thus, this study demonstrates that the presence of renal angiotensin-converting enzyme plays a pivotal role in the development of salt sensitivity in response to renal injury.

Angiotensin-converting enzyme overexpression in myelocytes enhances the immune response

Abstract Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.

Myeloid expression of angiotensin-converting enzyme facilitates myeloid maturation and inhibits the development of myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which accumulate in cancer, infection and chronic inflammation. These cells suppress T-cell function and the immune response. Angiotensin-converting enzyme (ACE) is a peptidase that is now known to regulate aspects of myelopoiesis. Here, we show that ACE expression correlates with myeloid maturation in vitro. Forced ACE overexpression in monocytic cells reduces the generation of MDSCs. In vivo, mice with a genetic change resulting in myeloid cell ACE overexpression have reduced numbers of blood and splenic MDSCs in a tumor model and in a model of chronic inflammation induced by complete Freund’s adjuvant. In contrast, ACE-null mice produce large numbers of MDSCs during chronic inflammation. Macrophages from mice with myeloid ACE overexpressing are more pro-inflammatory and have more tumor-killing activity than cells from wild-type mice. Thus, manipulating myeloid ACE activity can interfere with MDSC development and the maturation of myeloid cells.

ACE overexpression in myelomonocytic cells: effect on a mouse model of Alzheimer's disease.

While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice overexpress ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer’s disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-β protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD.