Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous evidence shows that salt-sensitive (S) rats have a net increase in plasma mineralocorticoid activity due to 18-hydroxy-11-deoxycorticosterone and decreased urinary kallikrein excretion compared to salt-resistant (R) rats. Since mineralocorticoids stimulate urinary kallikrein excretion, these results are inconsistent. This inconsistency was explained by the fact that, while R rats responded normally to treatment with deoxycorticosterone (DOC) by an increase in urinary kallikrein excretion, S rats showed no change in urinary kallikrein even when treated with 10 mg of DOC/day for 24 days. S and R rats responded identically to DOC with changes muscle electrolytes and relative hypertrophy of the renal distal tubule. Other measures of chronic mineralocorticoid response in S rats beside kallikrein were, therefore, intact. It was found that S rats were capable of responding to Na deficient diet with an increase in urinary kallikrein comparable to R rats. It was argued, therefore, that mineralocorticoid receptor mechanisms and distal-tubular cell responsiveness are intact in S rats. Mild glomerular and tubular scarring was found in S rats and the severity of renal lesions was increased by DOC treatment in S rats. These lesions correlated well with blood pressure and proteinuria. No such lesions were present in control or DOC treated R rats. It was suggested that failure of urinary kallikrein to respond to DOC in S rats may be a secondary phenomenon resulting from renal damage.
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PMID:Anomalous response of urinary kallikrein to deoxycorticosterone in Dahl salt-sensitive rats. 691 11

Chronic treatment of saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angiotensin II (Ang II) prevents the development of stroke and renal vascular damage. Ang II, in addition to its direct vascular effects, stimulates the synthesis and release of aldosterone. To assess the role of aldosterone in the development of pathologic changes in these rats, we implanted time-release pellets containing 200 mg of the mineralocorticoid receptor antagonist, spironolactone, into 14 SHRSP at 7.5 weeks of age. Eight SHRSP littermates received placebo pellets. Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) was not different between the groups. Spironolactone did not enhance water and electrolyte excretion. All placebo-treated SHRSP developed marked proteinuria (150+/-6 mg/d) whereas in spironolactone-treated SHRSP, urinary protein excretion (UPE) averaged 39+/-9 mg/d (P<.0001). In a second study to assess effects on survival, 6 SHRSP received spironolactone (10 mg/kg/d) and 6 received vehicle. All but one of the control rats displayed signs of stroke and died by 16 weeks of age, while the spironolactone-treated SHRSP remained asymptomatic through 19 weeks of age (P<.03). At 16 weeks of age, spironolactone-treated SHRSP were severely hypertensive (247+/-3 mm Hg), yet UPE remained at baseline levels. In contrast, preterminal UPE averaged 136+/-13 mg/d in control rats (P<.0001). In both studies, histopathologic examination revealed a marked protective effect of spironolactone against the development of malignant nephrosclerotic and cerebrovascular lesions. These observations indicate a vascular and end organ protective effect of spironolactone in the absence of lowered blood pressure in saline-drinking SHRSP and are consistent with a major role for mineralocorticoids as hormonal mediators of vascular injury.
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PMID:Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. 945 44

Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (n=8); captopril alone (50 mg. kg-1. d-1, orally) (n=10); aldosterone infusion alone (40 microg. kg-1. d-1, SC) (n=7); or captopril and aldosterone at 20 (n=6) or 40 (n=7) microg. kg-1. d-1. Systolic blood pressure was markedly elevated in all groups. Vehicle- and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21+/-3% and 29+/-3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 microg. kg-1. d-1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16+/-3% and 21+/-2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure.
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PMID:Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. 993 Nov 10

End-stage renal disease (ESRD) comprises an enormous public health burden, with an increasing incidence and prevalence. Hypertension is a major risk factor for progressive renal disease. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current antihypertensive approaches. Although much evidence demonstrates that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Several lines of experimental evidence demonstrate that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (i.e. remnant kidney). Whereas pharmacological blockade with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors reduces proteinuria and nephrosclerosis/ glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Aldosterone may promote fibrosis by several mechanisms, including plasminogen activator inhibitor-1 expression and consequent alterations of vascular fibrinolysis, by stimulation of transforming growth factor-beta 1, and by stimulation of reactive oxygen species. Based on this theoretical construct, randomized clinical studies will be initiated to delineate the potential renal-protective effects of antihypertensive therapy utilizing aldosterone receptor blockade.
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PMID:Aldosterone and the hypertensive kidney: its emerging role as a mediator of progressive renal dysfunction: a paradigm shift. 1139 64

End-stage renal disease (ESRD) comprises an enormous public health burden, with an incidence and prevalence that are increasingly on the rise. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current therapeutic approaches. Although much evidence demonstrates conclusively that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Recently, several lines of experimental evidence demonstrate that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat (SHRSP) model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (ie, remnant kidney). Whereas pharmacologic blockade with angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors reduces proteinuria and nephrosclerosis/glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Aldosterone may promote fibrosis by several mechanisms, including plasminogen activator inhibitor-1 (PAI-1) expression and consequent alterations of vascular ribrinolysis, by stimulation of transforming growth factor-beta1 (TGF-beta1), and by stimulation of reactive oxygen species (ROS). Based on this formulation, randomized clinical studies will be initiated to delineate the potential renal-protective effects of aldosterone receptor blockade.
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PMID:Aldosterone as a mediator of progressive renal dysfunction: evolving perspectives. 1150 95

Blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists has resulted in beneficial effects in essential hypertensive patients. However, occurrence of cardiovascular events has not been appropriately controlled beyond a certain percentage. One reason could be the effects of aldosterone, the final component of the system. The aldosterone escape phenomenon could explain undesirable outcomes observed in hypertensive patients even under treatment with ACE inhibitors or angiotensin antagonists. Aldosterone has direct effects on the vasculature and has been associated with vascular smooth muscle cell hypertrophy, endothelial dysfunction, cardiac fibrosis, proteinuria, and renal vascular injury. Animal models and clinical trials have proven the benefit of aldosterone receptor antagonism. With increased recognition of the prevalence of hyperaldosteronism in patients thought to have "essential" hypertension, the use of drugs that block aldosterone action may become more widespread and protect the vasculature from the deleterious effects of aldosterone.
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PMID:Aldosterone: a risk factor for vascular disease. 1253 Sep 37

Outcome studies in diabetic nephropathy have focused on strategies to prevent progression of diabetic nephropathy, the leading cause of ESRD in the United States. Once diabetics develop overt nephropathy, prognosis is poor. Risk factors for diabetic nephropathy are discussed, and include hyperglycemia, hypertension, angiotensin II, proteinuria, dyslipidemia, smoking, and anemia. Major outcomes as well as outcome studies in diabetic nephropathy for patients with microalbuminuria and macroalbuminuria are reviewed. Furthermore, the role of therapy with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and mineralocorticoid receptor antagonists as well as selected combination therapy are discussed. Recommendations for therapy with ace inhibitors and angiotensin II receptor blockers are made based on this evidence.
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PMID:Outcome studies in diabetic nephropathy. 1283 94

Angiotensin-converting enzyme inhibitors and aldosterone receptor antagonists ameliorate malignant nephrosclerotic lesions of thrombotic microangiopathy in salt-loaded, stroke-prone, spontaneously hypertensive rats (SHRSP) without controlling hypertension. This suggests that angiotensin II (Ang II) and/or aldosterone (ALDO) plays a critical role in renal injury in this model. For evaluating their relative roles in the pathogenesis of thrombotic microangiopathy, SHRSP were adrenalectomized and infused with vehicle, Ang II, or ALDO or were sham-operated for adrenalectomy (SHAM). Saline-drinking rats were assigned to one of four groups: SHAM, adrenalectomy, adrenalectomy + Ang II (25 ng/min, subcutaneously), or adrenalectomy + ALDO (40 micro g/kg per d, subcutaneously). All SHRSP received dexamethasone (12 micro g/kg per d, subcutaneously). Adrenalectomy did not show changes in body weight, plasma creatinine, sodium and potassium, and daily urinary sodium and potassium excretion; did not prevent hypertension but prevented proteinuria (12 +/- 1 versus 49 +/- 3 mg/d; P < 0.01); and abrogated thrombotic microangiopathy and decreased plasma aldosterone (<16 versus 710 +/- 91 pg/ml; P < 0.001) compared with SHAM. Systolic BP in adrenalectomy + Ang II and adrenalectomy + ALDO (238 +/- 8 and 241 +/- 9 mmHg, respectively) was similar to SHAM. Despite Ang II infusion, proteinuria (17 +/- 9 mg/d) and thrombotic microangiopathy and plasma aldosterone (18 +/- 18 pg/ml) remained low but daily urinary excretion of sodium and potassium were not different from adrenalectomy + ALDO. Adrenalectomy + ALDO showed plasma aldosterone levels of 735 +/- 147 pg/ml; plasma potassium was lower; plasma creatinine and proteinuria (78 +/- 7 mg/d) were greater and thrombotic microangiopathy lesions were comparable to SHAM. These results demonstrate a pivotal role for aldosterone in the development of thrombotic microangiopathy, independent of hypertension.
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PMID:Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. 1287 52

Aldosterone (Aldo) accelerates hypertension, proteinuria, and glomerulosclerosis in animal models of malignant hypertension or chronic renal failure. Aldo may exert these deleterious renal effects by elevating renal vascular resistance and glomerular capillary pressure. To test this possibility, directly examined were the action of Aldo on the afferent (Af) and efferent (Ef) arterioles (Arts). Examined were the effect of Aldo added to both the bath and lumen on the intraluminal diameter (measured at the most responsive point) of rabbits. Aldo caused dose-dependent constriction in both arterioles with a higher sensitivity in Ef-Arts. Vasoconstrictor action of Aldo was not affected by a mineralocorticoid receptor antagonist spironolactone and was reproduced by membrane-impermeable albumin-conjugated Aldo, suggesting that the vasoconstrictor actions are nongenomic. Pretreatment with neomycin (a specific inhibitor of phospholipase C) abolished the vasoconstrictor action of Aldo in both arterioles. In addition, the vasoconstrictor action of Aldo on Af-Arts was inhibited by both nifedipine and efonidipine, whereas that on Ef-Arts was inhibited by efonidipine but not nifedipine. The results demonstrate that Aldo causes nongenomic vasoconstriction by activating phospholipase C with a subsequent calcium mobilization thorough L- or T-type voltage-dependent calcium channels in Af- or Ef-Arts, respectively. These vasoconstrictor actions on the glomerular microcirculation may play an important role in the pathophysiology and progression of renal diseases by elevating renal vascular resistance and glomerular capillary pressure.
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PMID:Nongenomic vascular action of aldosterone in the glomerular microcirculation. 1293 1

Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.
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PMID:RAAS escape: a real clinical entity that may be important in the progression of cardiovascular and renal disease. 1294 34


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