Pathogenesis Of Malignant Hypertension Research Articles

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model

Background/Aims: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. Methods: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinβ₁ in addition to Angiotensin-II and TGF-β1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-β1 or receptor blockers. Results: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinβ₁, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-β1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. Conclusions: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-β1, culminating in apoptosis and detachment of non-viable podocytes.

Malignant hypertension: new aspects of an old clinical entity

Malignant hypertension (MHT), also known as accelerated-malignant hypertension or malignant-phase hypertension, is the most severe form of arterial hypertension. It is defined clinically as high blood pressure (BP) levels associated with lesions of the retinal fundus (flame-shaped hemorrhages, exudates, or cotton wool spots, with or without papilledema). Despite the availability of a vast range of antihypertensive agents, MHT continues to be a significant clinical challenge. Although its prevalence is very low, the absolute number of new cases has not changed over the past decades. While the role of the activation of the renin-angiotensin-aldosterone system and endothelial dysfunction in the pathogenesis of MHT has been well described, recent studies have indicated that the immune system may also play an important role in the development of this condition. Patients with MHT are characterized by pronounced target organ damage, including structural and functional cardiac abnormalities. MHT is frequently complicated by renal insufficiency and end-stage renal disease. The survival rates for patients with MHT have improved considerably with increased availability of antihypertensive treatment. However, renal insufficiency and end-stage renal disease still remain a significant cause of morbidity and mortality in this patient group. In conclusion, MHT is not a "vanishing disease" because there is a relatively stable number of new cases per year. Nonetheless, prognosis and survival rates in these patients have improved significantly owing to earlier detection, stricter BP control, lower BP targets, better choice of antihypertensive drugs, and availability of hemodialysis and renal transplantation.

Mesangial cells are responsible for orchestrating the renal podocytes injury in the context of malignant hypertension

Two populations of renal cells fully possess functional contractile cell apparatus: mesangial cells and podocytes. Previous studies demonstrated that in the context of malignant hypertension overproduction of Angiotensin-II by the contracting mesangial cells aggravated hypercellularity and apoptosis of adjacent cell populations. The role of podocytes in pathogenesis of malignant hypertension is unclear. We investigated responsiveness of normal vs. hyperglycaemic podocytes to pressure in a model of malignant hypertension. Rat renal podocytes and mesangial cells were subjected to high hydrostatic pressure, using an in vitro model of malignant hypertension. Part of them was pre-exposed to hyperglycaemic medium. Alternatively, the cells were cultured in conditioned medium collected from mesangial cells pre-exposed to pressure. Angiotensin-II was significantly increased in normoglycaemic mesangial cells subjected to pressure, triggering enhanced proliferation and apoptosis. No augmented Angiotensin-II, proliferation or apoptosis were evident in pressure-exposed normoglycaemic podocytes. In hyperglycaemic mesangial cells, but not podocytes, basal Angiotensin-II and apoptosis were augmented, along with abrogated proliferation. Challenge with exogenous Angiotensin-II or Angiotensin-II-containing conditioned medium, induced apoptosis both in podocytes and mesangial cells. 1. Unlike mesangial cells, podocytes do not respond to high pressure or hyperglycaemia per se. Resultantly, neither high pressure nor hyperglycaemia, trigger apoptosis of podocytes in vitro. However, surplus of Angiotensin-II, amply produced in vivo by the adjacent mesangial cells, would seem to be sufficient for initiating apoptosis of both mesangial cells and podocytes. 2. Hyperglycaemia abrogates cell replication. Resultantly, in diabetic patients regeneration of renal tissue damaged by the incidence of malignant hypertension may become compromised or completely lost.

Enrichment of (pro)renin receptor promoter with activating histone codes in the kidneys of spontaneously hypertensive rats

The (pro)renin receptor [(P)RR] non-proteolytically, through conformational change, activates prorenin which can convert angiotensinogen to angiotensin I in addition to the classic conversion of angiotensinogen to angiotensin I by circulating renin. Since renal (P)RR is upregulated in hypertension and implicated in the pathogenesis of malignant hypertension, we hypothesized that (pro)renin receptor promoter is enriched with activating histone codes in the kidney of spontaneously hypertensive rats (SHR). The mRNA and protein expression levels were measured by real-time polymerase chain reaction (PCR) and western blot, respectively. The DNA methylation status of (P)RR promoter region was analyzed by bisulfite sequencing. The histone modifications were determined by chromatin immunoprecipitation followed by real-time PCR. The (P)RR mRNA expression in the kidney was about six times greater in SHR than in Wistar-Kyoto (WKY) rats. The (P)RR promoter was little methylated in the kidneys of both WKY and SHR. Acetylated histone H3 (H3Ac) and di-methylated histone H3 at lysine 4 (H3K4me2), activating histone codes, were about 25 and three times higher in SHR than in WKY, respectively. On the other hand, di-methylated histone H3 at lysine 9 (H3K9me2), a suppressive histone code, was 50 times lower in SHR than in WKY. These results suggest that the (P)RR promoter is enriched with activating histone codes in the kidneys of SHR.

Protective effects of angiotensin AT 1 receptor blockade in malignant hypertension in the rat

We investigated the role of angiotensin II and endothelin-1 using the angiotensin AT 1 receptor antagonist losartan and the endothelin ET A receptor antagonist atrasentan, in malignant hypertension and renal failure and damage induced by nitric oxide (NO) synthase inhibition in Harlan Sprague–Dawley (SD) rats. We also evaluated whether the protective effects of losartan go beyond the blood pressure reduction. Within only 3 weeks of treatment with the NO synthase inhibitor N ω-nitro- l-arginine methyl ester ( l-NAME), Harlan SD rats developed malignant hypertension with renal failure and injuries. The latter were comprised of fibrinoid necrosis of small arteries and glomerular and tubular necrosis. Although both losartan and atrasentan attenuated the development of hypertension and renal failure, losartan only prevented the renal damage. In contrast to antrasentan, the vasodilator hydralazine reduced blood pressure and prevented the renal injuries similar to losartan. However, when these treatments were prolonged to 5 weeks, losartan, but not hydralazine, was still effective in reducing renal failure and damage, despite a marked increase in blood pressure. Our results indicate that angiotensin II and endothelin-1 play a differential role in the pathogenesis of malignant hypertension and in vascular and renal damage induced by l-NAME in Harlan SD rats. Although the protective effects of atrasentan may depend on the reduction of blood pressure, which was shown to retard the development of renal injury using hydralazine, those of losartan go beyond the blood pressure reduction. Hence, tissue protective effects of angiotensin AT 1 receptor blockade may be pivotal for long-term vascular and renal protection.

Enhanced angiotensin II production by renal mesangium is responsible for apoptosis/proliferation of endothelial and epithelial cells in a model of malignant hypertension

The systemic renin-angiotensin system (RAS) plays a crucial role in the pathogenesis of malignant hypertension. However, the intrarenal RAS might be at least equally important. We investigated the relationship between intrarenal RAS and mesangial, epithelial and endothelial cell proliferation/apoptosis in a model of malignant hypertension. Cultured murine mesangial cells were subjected to 160 mmHg hydrostatic pressure for 1 h. Angiotensin II was assessed by radio-immunoassay (RIA); pro-metalloproteinase-1 (pro-MMP-1) by enzyme-linked immunosorbent assay (ELISA); hydrogen peroxide (H2O2) by photocolorimetric assay, apoptosis by terminal dUTP (2-deoxyuridine 5'-triphosphate) nick-end labelling (TUNEL), p53 by western blot and proliferation by [H]thymidine incorporation, with or without angiotensin II and/or angiotensin II type 1/angiotensin II type 2 (AT-1/AT-2) receptor blockers. Endothelial and epithelial cells were similarly treated, and the same parameters evaluated. Further, untreated cells of both lines were cultured in conditioned medium of mesangial cells exposed to pressure. Their proliferation, apoptosis and angiotensin II production were also assessed. High hydrostatic pressure increased angiotensin II production by mesangial cells, coinciding with augmented apoptosis and proliferation. Co-stimulation with exogenous angiotensin II amplified both effects. Pressure per se evoked no response in endothelial/epithelial cells, while exogenous angiotensin II stimulated proliferation and apoptosis. No augmentation of p53 expression was evident. These effects were abolished by anti-angiotensin-II peptide, saralasine and losartan, but not by PD123319. Incubation of untreated cells in medium of mesangium subjected to pressure, augmented proliferation and apoptosis. No significant changes were noticed in pro-MMP or H2O2. Mesangium plays a deleterious role in the pathogenesis of malignant hypertension. High hydrostatic pressure stimulates angiotensin II synthesis by mesangial cells. The latter is responsible for hypercellularity and apoptotic death of mesangial, endothelial and epithelial cells. In this model, exaggerated apoptosis and proliferation are mediated via the angiotensin II pathway independently of p53 gene activation.

Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension

Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.

Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27.

Activation of the renin-angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin- -) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. Tissue renin-angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 microg/kg per day) from 28 to 120 days of age, untreated rats acting as controls (n = 40). The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treatment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. Sixty-three per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats. The degree of medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal 'vasculotoxic' agent in malignant hypertension.

Functional autoimmune epitope on α 1-adrenergic receptors in patients with malignant hypertension

Summary Because of the growing evidence that hypertensive disease is accompanied by immunological dysfunction, we have investigated autoimmunity in patients with malignant hypertension. Peptides corresponding to the sequences of the second extracellular loops of the human α 1-adrenergic receptor and the M 2-muscarinic receptor were used as antigens in an ELISA. Serum from 4 (12%) of 33 healthy controls, 3 (20%) of 15 patients with malignant essential hypertension, and 7 (64%) of 11 with secondary hypertension showed positive responses in the ELISA for the α 1-adrenergic receptor peptide. Positive responses were significantly more common among the patients with secondary hypertension than in the other two groups (p<0·01). By contrast, no autoantibodies against the M 2-muscarinic receptor peptide were detected in either hypertensive group. Autoantibodies against the α 1-adrenergic receptor, affinity-purified from patients with positive responses, specifically recognised bands with molecular masses of 68, 40, and 37 kDa on immunoblotted membrane proteins of rat ventricles. The patients' autoantibodies caused a decrease in tritiated prazosin binding sites and an increase in heart beating frequency of neonatal cultured rat cardiomyocytes; antibodies purified from the controls had no effect. Circulating autoantibodies against the α 1-adrenergic receptor are present in a subgroup of patients with malignant hypertension. These autoantibodies have pharmacological activity in vitro, which suggests that they may be involved in the pathogenesis of malignant hypertension.

Malignant hypertension: a syndrome accompanied by plasmatic diminution of low and high molecular weight kininogens.

Total kininogen (Kgn), kallikrein, and prekallikrein were measured in patients with malignant hypertension (MH), essential hypertension (EH), normotensive control (NC), and hypertension and chronic renal failure (HRF). These components of the kallikrein-kinin system were related to the levels of creatinine and fibrinogen. High molecular weight Kgn and low molecular weight Kgn were also measured in blood samples from a peripheral vein, arterial blood, and suprahepatic vein in NC, EH, and MH. Results showed that total Kgn levels were diminished in MH and this diminution could not be ascribed to decreases in renal function, hematocrit, or fibrinogen levels. Appropriate antihypertensive treatment for over 1 year did not normalize Kgn levels in 10 of 11 patients. High molecular weight Kgn and low molecular weight Kgn were both diminished in MH (0.26 +/- 0.04 nmol bradykinin/ml and 0.93 +/- 0.12 nmol lysyl-bradykinin/ml, respectively) as compared to NC (0.39 +/- 0.07 and 1.92 +/- 0.16) and EH (0.51 +/- 0.07 and 1.65 +/- 0.13). Higher concentrations of high molecular weight Kgn were demonstrated in the suprahepatic vein as compared to arterial blood, demonstrating its synthesis by the liver. However, patients with MH had a diminished capacity to synthetize high molecular weight Kgn. A decrease in synthesis of high molecular weight Kgn may be a partial explanation for low levels of total Kgn. It is suggested that a lack of Kgn may play a role in the pathogenesis of MH.

Does vasopressin play a role in the pathogenesis of hypertension?

1. Plasma levels of vasopressin were found to be significantly higher in 29 patients with malignant hypertension than in 106 normotensive control subjects (13 ± 2 ng/l vs 5.8 ± 0.2 ng/l, P &amp;lt; 0.001). 2. No correlation was apparent between blood pressure and circulating vasopressin. 3. An acute, incremental infusion of vasopressin (0.125, 0.25 and 0.5 ng min−1 kg−1) in nine patients with mild-moderate essential hypertension produced only minor changes in blood pressure despite achieving plasma levels spanning those seen in malignant hypertension. 4. Despite a small increase in pressor sensitivity to vasopressin in hypertensive subjects it is thus unlikely that an acute vasoconstrictor effect of this peptide is important in the pathogenesis of malignant hypertension.

Renin, angiotensin and aldosterone system in pathogenesis and management of hypertensive vascular disease

The renin angiotensin aldosterone concatenation, via two effector components, angiotensin II and aldosterone, simultaneously regulates (1) body sodium and water content, (2) arterial blood pressure and (3) potassium balance. Renin, secreted in response to stimuli which compromise kidney perfusion, increases plasma angiotensin and this stimulates aldosterone secretion. Vascular tone is regulated by an interaction between angiotensin levels and available (intravascular) sodium ions. The two hormones thus restore sodium balance and arterial pressure, thereby turning off renin release. Potassium homeostasis is maintained by two direct but opposing effects of plasma potassium levels on aldosterone and renin secretion. Derangements of this cybernetic system are involved in the pathogenesis of malignant hypertension, primary and pseudoprimary aldosteronism, renovascular hypertension and oral contraceptive hypertension. Subtler abnormalities in the renal adrenal axis occur in essential hypertension: Three major subgroups exhibit low (27 per cent), normal (57 per cent) or high plasma renin activity (16 per cent). When aldosterone is included, eight different hormonal profiles have been identified. Longitudinal studies indicate that, in contrast to groups with normal and high renin activity, patients with low renin essential hypertension appear to be protected from the development of strokes and heart attacks despite similar hypertension and cardiac enlargement and a higher age. Taken with the observations in malignant hypertension, plasma renin activity emerges as a risk factor predisposing to serious vascular injury. It thus may be a useful guide for determining etiology and prognosis. New therapeutic strategies are also suggested. Patients with low renin activity may not require early treatment whereas it should be diligently applied in those with high renin activity. Moreover, individualized antihypertensive therapy to correct specific derangements in the renin system holds special promise.

Chronic pyelonephritis lenta and the "malignant phase of hypertension".

In many texts on pathology and internal medicine, and even in recent publications, malignant nephrosclerosis is often regarded as the anatomical counterpart of malignant hypertension. Studying a number of such reports, we became aware that malignant nephrosclerosis cannot possibly be one single or one well-defined entity, since the descriptions of such kidneys are very much at variance, and since the various cases present somewhat different findings. As a matter of fact, changes characteristic of not only one but of several diseases may be found in some instances in one kidney. In recent years, there has been a guarded, but generally progressive, acceptance of pyelonephritis as a factor in the pathogenesis of malignant hypertension. 1 , 2 Recently, also, emphasis has been placed on the insidious course and the high incidence of urinary tract infections. 3-11 However, even in recent publications, the kidney lesions of most cases of malignant hypertension remain ascribed

A case of malignant hypertension, treated with prefrontal leucotomy and psychotherapy, followed for over eight years.

Abstract The authors describe a case of malignant hypertension treated with prefrontal leucotomy and psychotherapy. The operation took place on 5 April 1949. It was not followed by any immediate drop in blood pressure, but the patient became amenable to simple psychotherapy. In the following months and years the blood pressure dropped progressively until it reached high normal average values and the retinopathy and albuminuria disappeared. At present, eight years after the operation, the patient is still engaged in active work, although suffering from some after-effects of the operation. The authors discuss the importance of this observation for our insight into the aetiology and pathogenesis of malignant hypertension. It is suggested that the leucotomy did not act by a direct effect on the blood pressure, but by the changes it produced in the personality of the patient, especially in his attitudes towards certain of his, presumably specific, conflict situations.