Steven D. Crowley

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.

Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system

Angiotensin II, acting through type 1 angiotensin (AT(1)) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT(1) receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT(1A) receptor-deficient mice to demonstrate distinct and virtually equivalent contributions of AT(1) receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT(1A) receptors cannot be explained by altered aldosterone generation, which suggests that AT(1) receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT(1) receptor-mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT(1) receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT(1) receptors both within and outside the kidney.

Lymphocyte responses exacerbate angiotensin II-dependent hypertension

Activation of the immune system by ANG II contributes to the pathogenesis of hypertension, and pharmacological suppression of lymphocyte responses can ameliorate hypertensive end-organ damage. Therefore, to examine the mechanisms through which lymphocytes mediate blood pressure elevation, we studied ANG II-dependent hypertension in scid mice lacking lymphocyte responses and wild-type controls. Scid mice had a blunted hypertensive response to chronic ANG II infusion and accordingly developed less cardiac hypertrophy. Moreover, lymphocyte deficiency led to significant reductions in heart and kidney injury following 4 wk of angiotensin. The muted hypertensive response in the scid mice was associated with increased sodium excretion, urine volumes, and weight loss beginning on day 5 of angiotensin infusion. To explore the mechanisms underlying alterations in blood pressure and renal sodium handling, we measured gene expression for vasoactive mediators in the kidney after 4 wk of ANG II administration. Scid mice and controls had similar renal expression for interferon-gamma, interleukin-1beta, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-alpha, endothelial nitric oxide synthase (eNOS), and cyclooxygenase-2 (COX-2) in the kidney. In turn, this enhanced eNOS and COX-2 expression in the scid kidneys was associated with exaggerated renal generation of nitric oxide, prostaglandin E(2), and prostacyclin, all of which promote natriuresis. Thus, the absence of lymphocyte activity protects from hypertension by allowing blood pressure-induced sodium excretion, possibly via stimulation of eNOS- and COX-2-dependent pathways.

Effector mechanisms in transplant rejection

Summary:  Antigens, provided by the allograft, trigger the activation and proliferation of allospecific T cells. As a consequence of this response, effector elements are generated that mediate graft injury and are responsible for the clinical manifestations of allograft rejection. Donor‐specific CD8+ cytotoxic T lymphocytes play a major role in this process. Likewise, CD4+ T cells mediate delayed‐type hypersensitivity responses via the production of soluble mediators that function to further activate and guide immune cells to the site of injury. In addition, these mediators may directly alter graft function by modulating vascular tone and permeability or by promoting platelet aggregation. Allospecific CD4+ T cells also promote B‐cell maturation and differentiation into antibody‐secreting plasma cells via CD40–CD40 ligand interactions. Alloantibodies that are produced by these B cells exert most of their detrimental effects on the graft by activating the complement cascade. Alternatively, antibodies can bind Fc receptors on natural killer cells or macrophages and cause target cell lysis via antibody‐dependent cell‐mediated cytotoxicity. In this review, we discuss these major effector pathways, focusing on their role in the pathogenesis of allograft rejection.

Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha and the profibrotic cytokine transforming growth factor-beta. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

Kidney in Hypertension: Guyton Redux

Regulation of blood pressure is a complex integrated response involving a variety of organ systems including the central nervous system (CNS), cardiovascular system, kidneys, and adrenal glands. These systems modulate cardiac output, fluid volumes, and peripheral vascular resistance, the key determinants of blood pressure. More than 40 years ago, Guyton and Coleman1 developed computer models of arterial pressure control, attempting to incorporate the known variables impacting blood pressure homeostasis. The conclusion of this analysis was that regulation of sodium excretion by the kidney and consequent effects on body fluid volumes made up the critical pathway determining the chronic level of intra-arterial pressure. Our own studies of the physiology of blood pressure regulation have focused on the renin-angiotensin (Ang) system (RAS) using genetically modified mouse models. Highly conserved through phylogeny, the RAS is an essential regulator of blood pressure and fluid balance. This biological system is a multienzymatic cascade in which angiotensinogen, its major substrate, is processed in a 2-step reaction by renin and Ang-converting enzyme (ACE), resulting in the sequential generation of Ang I and Ang II. Along with its importance in maintaining normal circulatory homeostasis, abnormal activation of the RAS can contribute to the development of hypertension and target organ damage. The importance of the RAS in clinical medicine is highlighted by the impressive efficacy of pharmacological agents that inhibit the synthesis or activity of Ang II.2–5 At the cellular level, responsiveness to Ang II is conferred by expression of Ang receptors. Ang receptors can be divided into 2 pharmacological classes: type 1 (AT1) and type 2, based on their differential affinities for various nonpeptide antagonists.6,7 Studies using these antagonists suggested that most of the classically recognized functions of the RAS are mediated by AT1 receptors. Gene targeting studies confirmed these conclusions.8 AT …

Recent advances involving the renin–angiotensin system

Abstract The renin–angiotensin system (RAS) exercises fundamental control over sodium and water handling in the kidney. Accordingly, dysregulation of the RAS leads to blood pressure elevation with ensuing renal and cardiovascular damage. Recent studies have revealed that the RAS hormonal cascade is more complex than initially posited with multiple enzymes, effector molecules, and receptors that coordinately regulate the effects of the RAS on the kidney and vasculature. Moreover, recently identified tissue-specific RAS components have pleomorphic effects independent of the circulating RAS that influence critical homeostatic mechanisms including the immune response and fetal development. Further characterization of the diverse interactions between the RAS and other signaling pathways within specific tissues should lead to novel treatments for renal and cardiovascular disease.

Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

The inextricable role of the kidney in hypertension

An essential link between the kidney and blood pressure control has long been known. Here, we review evidence supporting the premise that an impaired capacity of the kidney to excrete sodium in response to elevated blood pressure is a major contributor to hypertension, irrespective of the initiating cause. In this regard, recent work suggests that novel pathways controlling key sodium transporters in kidney epithelia have a critical impact on hypertension pathogenesis, supporting a model in which impaired renal sodium excretion is a final common pathway through which vascular, neural, and inflammatory responses raise blood pressure. We also address recent findings calling into question long-standing notions regarding the relationship between sodium intake and changes in body fluid volume. Expanded understanding of the role of the kidney as both a cause and target of hypertension highlights key aspects of pathophysiology and may lead to identification of new strategies for prevention and treatment.

The Cooperative Roles of Inflammation and Oxidative Stress in the Pathogenesis of Hypertension

SIGNIFICANCE Innate and adaptive immunity play fundamental roles in the development of hypertension and its complications. As effectors of the cell-mediated immune response, myeloid cells and T lymphocytes protect the host organism from infection by attacking foreign intruders with bursts of reactive oxygen species (ROS). RECENT ADVANCES While these ROS may help to preserve the vascular tone and thereby protect against circulatory collapse in the face of overwhelming infection, aberrant elaboration of ROS triggered by immune cells in the absence of a hemodynamic insult can lead to pathologic increases in blood pressure. Conversely, misdirected oxidative stress in cardiovascular control organs, including the vasculature, the kidney, and the nervous system potentiates inflammatory responses, augmenting blood pressure elevation and inciting target organ damage. CRITICAL ISSUES Inflammation and oxidative stress thereby act as cooperative and synergistic partners in the pathogenesis of hypertension. FUTURE DIRECTIONS Pharmacologic interventions for hypertensive patients will need to exploit this robust bidirectional relationship between ROS generation and immune activation in cardiovascular control organs to maximize therapeutic benefit, while limiting off-target side effects.