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Abstract

The renin‑angiotensin‑aldosteron system (RAAS) is a hormonal system that contributes to regulation of blood pressure and volume of extracellular luids, in both nor‑ motensive and hypertensive individuals. Hypertension affects the target organs (kidneys) and leads to a vicious circle that contributes to maintaining a high arterial pre‑ ssure. Besides the hemodynamic effects of RAAS/Ang II, Ang II has direct impact on structure/function of kidneys, leading to renal injury. Recently, the proinlammatory effect of Ang II has been discovered. Low renal inlamma‑ tion determined by excessive circulating RAAS, mostly at renal level, promotes and continues the renal disease. This review presents the inlammatory mechanisms initiated by Ang II at renal level, which induce development of renal injury. Identiication of such mechanisms might lead to the discovery of new therapeutic approaches for hyperten‑ sion/target organs damage.

Keywords: RAAS, inlammation, renal injury, hyperten‑ sion

I. THE RENIN‑ANGIOTENSIN‑ALDOSTE‑ RON SYSTEM

Increased RAAS (renin‑angiotensin‑aldosteron system) activity, particularly at angiotensin II (Ang II) levels, contributes to target organ dam‑ age and increases the risk of cardiovascular events by increasing blood pressure, as well as by its direct effect on the vascular endothelium and cardiac and renal tissues [1], stimulating the

inlammatory phenomena and the development

of atherosclerosis [2]. Hypertension is closely related to renal disfunctions [3] and represents both the cause and effect of kidney diseases.

In 1871, Traube hypothesized that hyperten‑ sion may be a homeostatic response threatening

UPDATES OF THE RENIN‑ANGIOTENSIN‑ALDOSTERON SYSTEM

Minela MĂRĂNDUCĂ1, P. PLĂMĂDEALĂ2, Nina ZAMOSTEANU3, B. STOICA3,

Elena STEFANACHI4

1. Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, Faculty of Medicine, Dept. Morphofunctional Sciences

2. “St. Mary” Emergency Hospital for Children, Iasi, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, Faculty of Medicine, Dept. Morphofunctional Sciences

3. Discipline of Biochemistry, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, Faculty of Medicine, Dept. Morphofunctional Sciences

4. Discipline of Pathology, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, Faculty of Medicine,

Dept. Morphofunctional Sciences

Contact person: Petru Plămădeală: p_petru@yahoo.com

the excretory function of the kidney [4]. Exces‑ sive secretion of Ang II (antinatriuretic hormone) induces a transient increase in sodium retention. Physiologically, sodium retention becomes nor‑ mal in a few days, but there are situations when it is maintained at a high level, causing hyperten‑ sion. Ang II reduces the renal ability to excrete sodium and initiates a series of events that lead to increased blood pressure [5]. Increase in blood pressure, required to return to normal sodium excretion, is achieved by pressure – natriuresis phenomenon. The peripheral vascular resistance often increases in hypertension, although increased blood pressure is initiated by sodium retention and expansion of volume replacement. Increased blood pressure occurs due to direct and indirect effects of peripheral vasoconstrictor Ang II. Chronic administration of Ang II leads to increased sodium retention, developing severe systemic hypertension and pulmonary oedema.

Classically, the renin angiotensin system was considered a circulating hormone structure

whose inal and bioactive product, Ang II, is pro‑ duced with the participation of two important enzymes, renin and the angiotensin‑converting enzyme [6]. The renin‑angiotensin system is a hormonal complex with paracrine, autocrine and intracrine properties. Angiotensine is formed by

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angiotensin I (an apparently inactive decapep‑ tide). Angiotensin I is converted into a biologi‑ cally active molecule – angiotensin II (8 aminoacids) by the action of a glycoprotein released by lung tissue, the angiotensin‑convert‑ ing enzyme (ACE). Recently, a homologous angi‑ otensin‑converting enzyme called ACE2 was found in heart, kidney, liver, intestine. This new converting enzyme produces the hydrolysis of the last aminoacid of angiotensin I, leading to angiotensin (1‑9), a classical inhibitor of ACE1 and a precursor of angiotensin (1‑7). Angioten‑ sin‑(1‑9) may limit the formation and actions of

angiotensin II, contributing to local trafic

self‑regulation [6]. Also, angiotensin II can be generated from angiotensin I by the action of a large number of peptidases called chimase (alter‑ native ways of Ang II formation) [7]. As other peptide hormones, the angiotensins bind to membrane receptors on target cells to exercise their actions (type 1‑AT1 and type 2‑AT2 angio‑ tensin receptors). Classically, the most important function of RAAS is to maintain blood pressure by Ang II‑induced vasoconstriction and sodium retention, mediated by aldosterone in renal col‑ lecting tubules [8].

II. INTRARENAL RENIN‑ANGIOTENSIN SYSTEM

After more than two decades, a local RAAS that acts independently on the systemic RAAS has been described [9]. An exact delineation of the contribution of local and systemic angioten‑

sin peptides is dificult in terms of recent exper‑ iments. Every system in the body contains elements of RAAS. The excretory system (kid‑ neys) is the only one that possesses all RAAS components. In the last decade, Ang II is consid‑ ered a multifunctional cytokine with multiple non‑hemodynamic properties [10]. In addition to electrolytes homeostasis control, Ang II mediates

several key events in inlammatory processes [11]. In inlammatory processes, local RAAS acti‑ vation and synthesis of Ang II leads to increased vascular permeability by VEGF secretion (vascu‑

lar endothelium‑derived growth factor) [12‑14]

and induces the expression of adhesion molecu‑ les (L – selectins, P – selectins and ICAM‑1) and

their ligands (integrins) [15‑17]. Ang II promotes

inlammatory cell iniltration of tissues by stimu‑ lating the production of cytokines / chemokines. The renin angiotensin aldosterone system plays an essential role in pathological changes that lead to the progression of kidney disease. Renal injury activates directly and indirectly the local renin angiotensin aldosterone system. For example, hyperglycemia, proteinuria, reduced calcitriol can stimulate local Ang II synthesis

[18]. Inlammation, an early stage of kidney dam‑

age, is followed by tubulointerstitial ibrosis,

tubular atrophy and glomerulosclerosis [19].

III. PROINFLAMMATOY EFFECTS OF RAAS

Mononuclear cell iniltration of the glomeruli

and interstitium is present in most renal diseases and plays a crucial role in the development of irreversible structural changes. Immunocompe‑ tent cells (T lymphocytes, macrophages and den‑ dritic cells) contain components of the RAAS and contribute to the production of Ang II [20‑22].

RAAS plays an essential role in leukocyte inil‑

tration and thus it can inluence the evolution of

many renal diseases associating immune activa‑ tion [23].

Ang II is involved in inlammatory processes

occurring during kidney damage by regulating the expression of adhesion molecules. Ang II is

a chemotatic factor for inlammatory cells,

increasing the expression of chemokines and chemokine receptors in both resident cells and

iniltrated cells [20]. The inlammatory response

can be direct ‑ through the production of MCP‑1

and TGF‑β1, and indirect ‑ by activating resident cells by macrophages released factors [24].

By AT 1 and AT 2 receptors pathways, Ang II stimulates transcription of the NF‑KB factor. Ang IV has a similar effect. Angiotensin receptor antagonists (sartans) can block only certain pro‑

inlammatory effects of RAAS. The NF‑KB factor

activation caused by Ang II occurs via the Rho kinase way.

Ang II stimulates the Ets factor transcription

that is the main regulator of vessel iniltration

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mechanism involved in the development of renal

inlammation in response to Ang II involves the participation of Toll‑like receptor 4 of mesangial cells. An increase in Toll‑like receptors 4, medi‑ ated by Ang II, results in activation of the NF‑KB factor [26].

The essential role in the progression of renal

disease is played by recruitment of inlammatory

cells in glomeruli and tubular interstitium. Ang II stimulates the growth of VECAM‑1 number (vascular cell adhesion molecule‑1), ICAM‑1 (intercellular adhesion molecule‑1), and integ‑ rins, and allows the circulating immune cells to adhere to the capillaries.

The NF‑KB factor mediates the transcription of chemokine genes responsible for the renal tis‑

sue leukocytes iniltration, that include: MCP‑1

(monocyte chemotactic protein‑1), RANTES. Ang II can directly stimulate cell proliferation [27]. Leukocytes are an active source of Ang II,

thus amplifying the proinlammatory effects [28]. Ang II‑mediated proinlammatory effects

increase the pathophysiological changes caused by proteinuria [10].

III.1. THE ROLE OF ANGIOTENSIN AND NF‑KB FACTOR IN THE INFLAMMATORY RESPONSE

Ang II plays a special role in the development

of inlammation in the kidney. The main vasoac‑ tive peptide of RAAS causes migration and adherence of the circulating immune cells in the kidney, at both endothelial and mesangial level. This process involves adhesion of the cytokines and chemokines molecules [29]. On experimen‑ tal animal models with kidney diseases, admin‑ istration of angiotensin converting enzyme

inhibitors (ACEI) results in decreased cell inil‑

tration and inlammatory markers [29].

By activating the AT1 receptor, Ang II increases

the expression of proinlammatory genes for

VCAM‑1, ICAM‑1, IL‑6 and MCP‑1. The signal‑ ing pathways by which these effects are achieved include activation of the NF‑KB factor, MAP‑ kinase cascade, Rho protein and redox pathways.

Experimental data show that AT2 receptors

are involved in the activation of inlammatory

cells in the kidney. The AT2 receptor antagonists,

but not the AT1 receptor, decrease the number

of inlammatory cells in two animal models of

unilateral urethral obstruction receiving sys‑ temic Ang II [29‑31].

The combined treatment with AT1 and AT2

receptor antagonists inhibits the inlammatory

response by two mechanisms: decrease of cell

iniltrate and decreased expression of proinlam‑ matory genes.

On unilateral urethral obstruction model,

blocking of the AT2 receptor decreases TNF‑α

and expression of RANTES; stimulation of both types of receptors decreases gene expression, which increases MCP‑1 [30]. Involvement of NF‑KB is known in renal disease. In vivo activa‑ tion of the NF‑KB factor, produced as a response to Ang II, is partially diminished by AT1 and AT2 receptor antagonists. In contrast, simultane‑ ous administration of both types of receptor antagonists or ECAI totally abolishes this response [29‑31]. The NF‑KB factor activation in the kidney is differently mediated, according to the place where it occurs. Therefore, in mesan‑ gial cells, it is mediated by both types of recep‑ tors, in tubulo‑interstitial cells only by AT1 receptors, while, in the endothelial cells ‑ via the AT2 receptor.

On the unilateral urethral obstruction model, blocking of the renal NF‑KB factor activation by treatment with two different renal inhibitors (pyrrolidin dihydrocarbonate and partenolide)

decreases the iniltration with inlammatory cells and the gene expression of some pro‑inlamma‑ tory factors.

In spontaneously hypertensive rats, inhibition of the NF‑KB factor results in the decrease of

iniltration with inlammatory cells in renal inter‑ stitium and normalization of blood pressure. These data support the hypothesis that, in some experimentally‑induced renal disease, blocking of Ang II with ACEI and antagonists of angio‑ tensinic receptors (AT1 and AT2), and inhibition of NF‑KB pathways are necessary to stop the

inlammatory processes.

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III.2. INFLAMMATION AND RENAL INTERSTITIUM

Ang II acts as a cytokine mediating the inil‑ tration and activation of immunocompetent cells in the renal interstitium. Immunocompetent cell

iniltration of the renal interstitium is present in

non‑immune primary injury (the disease evolves with proteinuria, urinary obstruction, polycystic kidney disease, diabetes, hypertension). Mono‑

nuclear cell iniltration occurs in the absence of a speciic antigen and is the result of increased

expression of chemoatractant molecules [22,23]. Under pathological conditions, an increased activation of the RAAS, especially in the tubular cells, may be observed. A decrease in renal inter‑

stitium iniltration is achieved by blocking the

RAAS (antisense oligonucleotides and drugs). This phenomenon is partially due to decreasing of chemokines (MCP‑1 and osteopontin), adhe‑ sion molecules and other mediators. Ang II pos‑ sesses chemotatic properties for mononuclear cells. Tubular RAAS activation leads to an

increase in local interstitial iniltration. Mice with a deicit of AT1 receptor and a high level of pro‑

teinuria show a marked interstitial iniltration,

that is not reduced after ACEI administration.

Instead, there is a signiicant decrease in cellular iniltration after an antagonist of A/B endothelin

receptor administration. Ang II stimulates the expression of endothelium. This suggests that other mediators, including vasoactive peptides, endothelin, are involved in interstitial cell recruit‑ ment [32].

Johnson et al. hypothesized that sodium‑sen‑ sitive hypertension appears as the result of tub‑ ulo‑interstitial damage, interferring with the physiological mechanisms of pressure‑natriure‑ sis type. This phenomenon has been studied extensively by the use of Ang II in hypertensive models, due to a massive intake of sodium. The conclusion was that Ang II is the key mediator involved in cell recruitment. Administration of mycophenolate mofenil prevents this type of

hypertension and markedly reduces cell iniltra‑ tion of the interstitium [33].

Chronic administration of L‑NAME reduces the synthesis of nitric oxide and the development

of hypertension. At interstitial level, an iniltra‑ tion with macrophages and lymphocytes occurs.

When the chronic L‑NAME administration is interrupted, normalization of blood pressure is observed, to a lower extent for the animals hav‑ ing received a hypersodate diet during hyperten‑ sion. Interestingly, both sodium‑dependent hypertension models showed a high level of Ang II‑producing cells, particularly lymphocytes, accumulated in the renal interstitium. Adminis‑ tration of mycophenolate mofenil led to stabili‑ zation of blood pressure and decrease of oxidative

stress [34].

In conclusion, the immune cells are capable of producing Ang II in various stages of renal impairment, playing therefore an important role in sodium‑sensitive hypertension [35].

The immunocompetent cells recruited by the

inlammed interstium can synthesize Ang II that

locally induces differentiation of antigen pre‑ senting cells and increases their antigenic activ‑ ity.

III.3. INFLAMMATION AND RENAL GLOMERULUS

Local RAAS ampliies the antigen‑speciic

immune response in renal glomerular diseases. Ang II is involved in the pathogenesis of the immune complex mediated glomerulonephritis, by activating the NF‑KB factor, MCP‑1 produc‑ tion and expression of adhesion molecules [36‑38]. In glomerulonephritis, the renal RAAS

mediates antigen‑speciic T cell activation. In

anti‑glomerular basement membrane glomeru‑ lonephritis (anti‑GMB GN), both humoral and cellular immunity are involved. In acute glomer‑ ular injury, the immunoglobulin Fc receptor plays a critical role in PMN recruitment [39]. It

was observed that mice deicient in Fc receptor [γ (–/–)] showed protection against primary

lethal injury, but still developed glomerular injury characterized by: mesangial proliferation, accumulation of macrophages and formation of deposits in the basement membrane. These changes are prevented by AT1 receptor antago‑ nists administration [35].

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RASS in a dose‑dependent manner. In vivo and in vitro studies have demonstrated that Ang II plays an important role in lymphocytic prolif‑ eration, mostly of Th1 lymphocytes. However, the contribution of systemic RAAS to the devel‑ opment of glomerulonephritis mediated by T cells is not fully understood. There is a large functional diversity between Th1 and Th2 lym‑ phocytes, which is partially explained by the dif‑

ferent phenotypes of chemokine receptors [40].

Administration of Ang II in mesangial cells has a potent chemotatic effect for T cells. At this level, Ang II enhances the expression of

chemokines IP‑10 and MIP1α.

In glomerulonephritis with immune com‑ plexes, local RAAS may contribute to the occur‑

rence of antigen‑speciic T lymphocytes in inlammated glomeruli. The mechanism under‑ lying this phenomenon is achieved, at least par‑ tially, through chemokines regulation. The appearance of cellular response to Ang II is achieved through different molecular pathways, which include calcium mobilization, generation of free radicals, activation of protein kinases and

nuclear transcription factors [41].

Inlammatory processes caused by Ang II are

achieved through the NF‑KB factor, which rep‑ resents the key mediator of these processes. Under its control, Ang II causes an increase in

the cytokines and chemokines proinlammatory

genes. The NF‑KB factor activation pathway involves both types of angiotensin receptors, AT1 and AT2. The pathways by which Ang II activates the Th1 type chemokines are differently regulated. IP‑10 is NF‑KB dependent, whereas

MIP‑1α is regulated mainly by NF‑AT (nuclear

factor calcineurin‑dependent on the T activated cells). The NF‑AT activity requires a higher con‑ centration of calcium, realized by a massive influx through calcium release‑dependent (ICRAC) and calcineurin‑ dependent (CaN) channels.

The NF‑AT pathway activated by Ang II may be involved in pathological changes of vascular smooth muscle cells. CaN / NF‑AT are involved in Ang II‑induced lymphocytic proliferation, while the Ang II / NF‑AT pathway might be

involved in tubulo‑interstitial damage [42]. Acti‑ vation of NF‑AT was observed in tubulo‑inter‑

stitial iniltration of chronic glomerulonephritis

with anti ‑ basement membrane antibodies and

proteinuria in mice γ (–/–).

In conclusion, Ang II acts as a mediator of

inlammation, being partially involved in the pathogenesis of kidney disease by iniltration

and activation of immunocompetent cells. In some kidney diseases, the immune system can

be directly inluenced by local RAS activation.

PERSPECTIVES

The synthesis of the irst oral inhibitor of ACE,

captopril, urged the development of new thera‑ peutic hypotheses and opened a new stage in clinical research of RAAS. Blocking of RAAS

with IACE has been showed as very eficient in

the treatment of hypertension. Subsequently, the

hypertensive patients beneit from the discovery

of Ang II antagonists discovery, which selec‑ tively block the activation of AT1 receptors,

without inluencing vase‑dilatation kinines. Use of anti‑inlammatory medication or blocking of inlammatory cytokines in hypertension may

represent a new therapeutic approach in renal disease.

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