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PubMed1994

Are renal hemodynamics a key factor in the development and maintenance of arterial hypertension in humans?

The kidney plays a key role in the control of body fluids and blood pressure. Evidence has shown that impairment of renal function can lead to the development of arterial hypertension. The regulation of renal blood flow appears to be a key element in the pathophysiology of the hypertensive process, because multiple evidence suggests the existence of a functional enhancement of renal vascular tone in this disorder. The existence of renal vasoconstriction and of an inherited defect in the regulation of renal blood flow has been proposed in the prehypertensive stage. The mechanisms responsible for this alteration include a lack of modulation of the renal vasculature to angiotensin II, increased sympathetic activity, or suppressed renal dopaminergic activity. Established hypertension is characterized by elevated renal vascular resistance, decreased renal blood flow, sustained glomerular filtration rate, and increased filtration fraction. The increase in renal vascular resistance is initially due to elevations in renal vascular tone and is reversible, whereas later it becomes irreversible because of structural changes involved in nephrosclerosis. Antihypertensive drugs are able to decrease blood pressure and to prevent the development of further renal vascular damage independently of variable effects on renal hemodynamics.

Antihypertensive Agents↗

PubMed1995

Effect of captopril and angiotensin II receptor blockade on pressure natriuresis in transgenic TGR(mRen-2)27 rats.

The pressure-natriuresis curve of transgenic rats harboring an extra mouse renin gene [TGR(mRen-2)27] is shifted rightward compared with controls; however, whether intrarenal angiotensin II effects are responsible for the rightward shift is unknown. To clarify this issue we infused the converting enzyme inhibitor captopril or the angiotensin II receptor blocker CV 11974 into transgenic and normotensive Sprague-Dawley Hannover control rats. We eliminated any other neural or endocrine regulatory differences between transgenic and control rats by renal denervation and infusion of vasopressin, aldosterone, corticosterone, and norepinephrine in sufficient quantities to occupy all receptors. Sodium excretion increased from 3.4 +/- 1.2 to 10.1 +/- 0.5 mumol/min per gram kidney weight in transgenic rats when renal perfusion pressure was increased from 158 to 201 mm Hg. Captopril (4 mg/kg) and CV 11974 (0.1 mg/kg) shifted the pressure-natriuresis curve of transgenic rats leftward, so that sodium excretion was threefold higher at similar renal perfusion pressures (150 to 160 mm Hg). Similarly, fractional sodium and water excretion curves were shifted leftward, so that values for transgenic and control rats were no longer different. Over the pressure range, renal blood flow in transgenic rats ranged from 3.1 +/- 0.7 to 4.4 +/- 0.5 mL/min per gram kidney weight and increased (P < .05) with both captopril and CV 11974 to ranges from 4.8 +/- 0.9 to 6.8 +/- 0.6 or from 4.5 +/- 0.7 to 6.9 +/- 1.0 mL/min per gram kidney weight, respectively. Glomerular filtration rate in transgenic rats, on the other hand, was not increased. Transgenic kidneys showed severe hypertension-induced nephrosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1996

Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension.

The objective of this study was to determine whether the calcium antagonist amlodipine could slow the progression of chronic renal disease. We examined the effects of amlodipine on kidney structure and function in two experimental models of hypertension. In the first study, adult, male Munich Wistar rats underwent uninephrectomy and were given weekly injections of desoxycorticosterone and 1% saline for drinking. Rats ingested normal chow or chow containing amlodipine for 8 weeks. The drug reduced systemic blood pressure, but glomerular filtration rate, kidney weight, proteinuria, and morphological evidence of glomerular injury were not affected. In the second study, male spontaneously hypertensive rats underwent uninephrectomy at 5 weeks of age and were followed for 6 months, during which they received no therapy or amlodipine. The drug dose was determined in preliminary studies to be the highest dose not associated with marked growth retardation. Again, although systemic blood pressure was significantly reduced by amlodipine, proteinuria and the prevalence of glomerulosclerosis were similar in amlodipine-treated and control spontaneously hypertensive rats. Micropuncture studies revealed that glomerular pressure remained elevated in amlodipine-treated spontaneously hypertensive rats. Kidney weight and glomerular volume were also similar in amlodipine-treated and control rats. Amlodipine also failed to inhibit platelet aggregation. Therefore, antihypertensive therapy with amlodipine fails to reduce glomerular pressure in spontaneously hypertensive rats as well as glomerular size and injury in spontaneously hypertension rats and desoxycorticosterone-salt hypertension. Although other dihydropyridine calcium antagonists have been found to reduce experimental glomerular injury, these data suggest that amlodipine may not prevent hypertensive nephrosclerosis.

Amlodipine↗

PubMed2001

Abnormal renal vascular responses to dipyridamole-induced vasodilation in spontaneously hypertensive rats.

The objective of this study was to determine whether there were differences in hemodynamic responses of different vascular beds to systemic administration of dipyridamole between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. To this end, systemic hemodynamics and organ blood flows (using labeled microspheres) were determined in conscious rats before and 10 minutes after dipyridamole (4 mg. kg(-1). min(-1)) infusion. In both the normotensive and hypertensive rats, the dipyridamole infusion reduced arterial pressure by approximately 20 mm Hg, associated with a decreased total peripheral resistance and an increased cardiac output. Renal blood flow decreased significantly in SHR after dipyridamole but remained unchanged or increased slightly in the WKY rats. There were no other differences in regional hemodynamics, including those of brain, liver, skin, and muscle, between the WKY and SHR. Antihypertensive treatment completely restored normal renal vascular response to dipyridamole. Previous reports had demonstrated an abnormal coronary hemodynamic response of the SHR. Our data demonstrate that, as with coronary hemodynamics, hypertension selectively induced alterations in renal vasculature. These findings may be of importance in identifying the earliest hemodynamic evidence of developing hypertensive nephrosclerosis.

Animals↗

PubMed1978

Failure of renin suppression by angiotensin II in hypertension.

Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.

Adult↗

PubMed2005

Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria.

BACKGROUND: Aldosterone has emerged as a deleterious hormone in the heart, with mineralocorticoid receptor (MR) blockade reducing mortality in patients with severe heart failure. There is also experimental evidence that aldosterone contributes to the development of nephrosclerosis and renal fibrosis in rodent models, but little is known of its role in clinical renal disease. METHODS AND RESULTS: We quantified MR, serum- and glucocorticoid-regulated kinase 1 (sgk1), and mRNA expression of inflammatory mediators such as macrophage chemoattractant protein-1 (MCP-1), transforming growth factor-beta1, and interleukin-6 in 95 human kidney biopsies in patients with renal failure and mild to marked proteinuria of diverse etiologic origins. We measured renal function, serum aldosterone, urinary MCP-1 protein excretion, and the amount of chronic renal damage. Macrophage invasion was quantified by CD68 and vascularization by CD34 immunostaining. Serum aldosterone correlated negatively with creatinine clearance (P<0.01) and positively with renal scarring (P<0.05) but did not correlate with MR mRNA expression or proteinuria. Patients with heavy albuminuria (>2 g/24 h; n=15) had the most renal scarring and the lowest endothelial CD34 staining. This group showed a significant 5-fold increase in MR, a 2.5-fold increase in sgk1 expression and a significant increase in inflammatory mediators (7-fold increase in MCP-1, 3-fold increase in transforming growth factor-beta1, and 2-fold increase in interleukin-6 mRNA). Urinary MCP-1 protein excretion and renal macrophage invasion were significantly increased in patients with heavy albuminuria. CONCLUSIONS: These studies support animal data linking aldosterone/MR activation to renal inflammation and proteinuria. Further studies are urgently required to assess the potential beneficial effects of MR antagonism in patients with renal disease.

Adolescent↗

PubMed2001

Angiotensin II type 1 receptor blockade prevents lethal malignant hypertension: relation to kidney inflammation.

BACKGROUND: Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect. METHODS AND RESULTS: Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg. kg(-1). d(-1) or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects. CONCLUSIONS: Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.

Angiotensin Receptor Antagonists↗

PubMed2002

Lipocalin-type prostaglandin d synthase in essential hypertension.

Lipocalin-type prostaglandin D synthase (L-PGDS) reportedly well predicts cardiovascular injuries in humans. However, little is known about the implications of L-PGDS in hypertension. In the present study, we investigated the alterations of serum and urinary L-PGDS in hypertensive patients with or without renal dysfunction. A total of 111 patients with hypertension (EHT; 65 with normoalbuminuria, 23 with microalbuminuria, 12 with macroalbuminuria, 11 with renal failure) and 102 normotensive, nomoalbuminuric subjects (NT) were studied. L-PGDS was measured by enzyme-linked immunosorbent assay, and L-PGDS in the kidney was localized using immunohistochemical methods. Blood pressure was higher in EHT groups than in the NT group (P<0.0001). There were no differences in age, gender, BMI, TC, TG, and HbA1c levels among the groups. Serum creatinine and urinary albumin levels were higher in the group with renal failure. Serum levels of L-PGDS were increased in EHT with normoalbuminuria, as compared with NT (0.88 +/- 0.05 versus 0.65 +/- 0.02 microg/mL; P<0.001). Serum levels of L-PGDS increased with the renal function worsened and positively correlated with serum creatinine, particularly in patients with renal impairments (r=0.76, P<0.0001). Similarly, the urinary L-PGDS excretions in EHT with normoalbuminuria were higher than that in NT (2.31 +/- 0.29 versus 1.16 +/- 0.14 mg/gCr, P<0.001), whereas there were no differences in urinary albumin excretion between the 2 groups. Moreover, urinary L-PGDS excretion increased dramatically with an increase in albuminuria or proteinuria. L-PGDS was stained in the tubules and the interstitium of the kidney in nephrosclerosis. In conclusion, patients with hypertension exhibited a higher level of L-PGDS in serum and urine, and this became increasingly obvious along with advance in renal dysfunction. These data suggest that L-PGDS metabolism is related to blood pressure and kidney injuries associated with hypertension.

Carrier Proteins↗

PubMed2001

Apoptosis and glomerular injury after prolonged nitric oxide synthase inhibition in spontaneously hypertensive rats.

This study was designed to investigate the relationship between apoptosis and glomerular injury in spontaneously hypertensive rats (SHR) with hypertensive disease that was exacerbated by inhibition of NO synthesis. Development of glomerular cell apoptosis was evaluated by assessment of renal hemodynamics, glomerular morphometric changes, and participation of the renin-angiotensin system. Three groups of 20-week-old SHR were investigated: control male SHR and 2 similar groups given 2 doses of N(G)-nitro-L-arginine methyl ester (L-NAME, 50 or 80 mg/L, respectively) for 3 weeks. Mean arterial pressure and renal vascular resistance increased, whereas effective renal plasma flow and glomerular filtration rate were diminished by L-NAME. The small artery wall/lumen ratio increased as the glomerular-tuft area diminished. Renal cortical tissue levels of angiotensin II increased in response to the L-NAME, thereby inducing afferent arteriolar injury. Apoptosis and proliferative index (PCNA) of nonsclerotic glomeruli were induced by the low-dose L-NAME as the glomerular cell number decreased. In contrast, the PCNA index was downregulated with the high-dose L-NAME. These results indicate that angiotensin II activation, induced by L-NAME, was related to glomerular cell deletion and apoptosis together with the pathophysiological changes of severe nephrosclerosis and impaired renal dynamics.

Angiotensin II↗

PubMed1983

An autopsy case of 17 alpha-hydroxylase deficiency with malignant hypertension.

This is the first autopsy case of male 17 alpha-hydroxylase deficiency with malignant hypertension. The subject had hypertension, hypokalemic alkalosis, and pseudohermaphroditism. At age 21, 17 alpha-hydroxylase deficiency was diagnosed by low urinary excretion of 17-hydroxysteroids, low secretion rate of cortisol, and low plasma testosterone level in association with high urinary excretion of pregnanediol and high plasma progesterone and corticosterone. Urinary excretion of aldosterone and PRA were suppressed, and plasma ACTH was elevated. Hypertension and hypokalemic alkalosis were normalized with dexamethasone therapy. After missing 5 yr of follow-up, malignant hypertension developed, and PRA and aldosterone were elevated. Histological examination revealed some characteristic arteriolar lesions as in malignant nephrosclerosis. Juxtaglomerular hyperplasia and an increase of renin granules were observed, which reflected high PRA. Abnormal histological findings of endocrine organs were observed in the breast, the pituitary gland, the adrenal glands, and the testis.

Adrenal Hyperplasia, Congenital↗

PubMed1985

Chronic effects of a beta-adrenoceptor blocking drug, 4-[3-(tert-butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril hydrochloride (N-696), in hypertensive rats.

4-[3-(tert-Butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril hydrochloride (N-696) is a new beta-adrenoceptor blocking drug with direct vasodilatory activity, and may be classified into the fourth generation. Antihypertensive effects of N-696 were studied for 12 weeks in spontaneously (SHR), two kidney, one clip (CLIP), and deoxycorticosterone-salt (DOC) hypertensive rats. Propranolol (PPL) was used as the reference drug. In indirect blood pressure (BP) determination at the tail, milder prewarming condition was employed to observe antihypertensive effects clearly. Rats were prewarmed in rat holders on a hot plate for 30-60 min. Surface temperature of the hot plate was 35-45 degrees C. N-696 (20 mg/kg per day p.o.) and PPL (100 mg/kg per day, p.o.) treatments significantly decreased heart rate (HR) and maximum BP determined indirectly in SHR rats, even at the early stage of the experiments. These antihypertensive effects were shown also by mean BP determined directly at the 12th week. N-696 and PPL treatments showed no significant antihypertensive effects in CLIP rats, and slight antihypertensive effects in DOC rats. N-696 treatments showed a tendency to decrease plasma renin concentration (PRC) in SHR and DOC rats, whereas PPL treatments significantly decreased PRC in these hypertensive rats. N-696 and PPL treatments prevented nephrosclerosis and vascular lesions in SHR and DOC rats only slightly.

Adrenergic beta-Antagonists↗

PubMed1997

[Role of the renin-angiotensin system in cardiovascular and renal diseases].

Accumulating evidence indicate that various growth-related genes, growth factors and extracellular matrix components play a central role in the pathogenesis of cardiovascular and renal diseases by regulating cellular phenotype, growth and migration or promoting tissue fibrosis. Treatment of hypertensive rats with an angiotensin II type 1-receptor (AT1-receptor) antagonist normalizes cardiac phenotypic modulation and the increased fibrosis-related gene expressions in hypertrophied heart, leading to the improvement of cardiac dysfunction. The AT1-receptor antagonist can inhibit protooncogenes (c-fos, c-jun and Egr-1) and fibronectin gene expressions in rat balloon-injured artery, which is associated with the inhibition of neointima formation. Furthermore, the AT1-receptor antagonist prevents either the phenotypic modulation of glomerular mesangial cells or the increase in transforming growth factor-beta 1 expression in nephrosclerosis. Thus, the AT1-receptor antagonist in vivo potently inhibits the expression of growth-related gene and extracellular matrix and inhibits cellular phenotypic modulation. The AT1-receptor is responsible for the pathogenesis and development of cardiovascular and renal diseases.

Angiotensin Receptor Antagonists↗

PubMed1985

Chronic effects of enalapril on blood pressure, stroke, plasma renin, urinary electrolytes and PGE2 excretion in stroke-prone spontaneously hypertensive rats.

Antihypertensive effect of enalapril (MK-421), an orally active non-sulfhydryl-containing converting enzyme inhibitor, was examined in stroke-prone spontaneously hypertensive (SHRSP) rats. The treatment was started at 14-15 weeks of age with tail blood pressure over 240 mmHg and was continued for 11 weeks. We used captopril as the reference drug. The dose of enalapril and captopril was 10 and 30 mg/kg per day, p.o., respectively. Enalapril showed a sustained antihypertensive effect from the 1st to the 11th week of the treatment. This antihypertensive effect was substantiated by the good increase in body weight; decrease in heart weight; decrease in incidences of vascular disease, nephrosclerosis, stroke and death. Enalapril treatment also prevented the increases in urine volume, and excretion of osmotically active solutes, Na, Cl and K with age. Captopril treatment showed about the same antihypertensive effect. No side effects were seen in the enalapril or captopril treated group. The antihypertensive potency of enalapril was about 3 times more than that of captopril. Enalapril and captopril slightly increased plasma renin concentration. Urinary excretion of PGE2 was not changed by enalapril or captopril treatment. These results clearly demonstrate the efficacy of long-term treatment with enalapril to prevent development of malignant hypertensive cardiovascular disease in SHRSP rats.

Animals↗

PubMed1987

Age-related non-neoplastic lesions in the heart and kidneys of Syrian hamsters of the APA strain.

Spontaneous cardiac and renal lesions in APA hamsters were examined histopathologically. Myocardial degeneration, valvular thickening, coronary arterial degeneration and increase in heart weight were common in old hamsters. These changes, which suggest cardiac failure, seem to be related to cardiac thrombosis which predominantly affected the left atrium and was found in over 40% of each sex over 16 months of age. Neither glomerular amyloidosis nor arteriolar nephrosclerosis was detected. In general the histopathology of renal lesions in APA hamsters resembled that of the condition known as glomerulonephrosis in rats. Renal lesions occurred more frequently and more severely and developed more rapidly in females than in males. There was no apparent correlation between cardiac thrombosis and renal disease.

Aging↗

PubMed2006

Impact of hypertension and hypertension-related vascular lesions in IgA nephropathy.

It remains poorly understood whether vascular pathology plays an important role in the progression of renal parenchymal disease in humans. Moreover, in the case of hypertensive patients with mild proteinuria, nephrologists tend to make a diagnosis of benign nephrosclerosis without renal biopsy. Among 172 patients who were treated at our hospital for biopsy-proven IgA nephropathy, we performed quantitative histopathological analysis in 38 patients with mild proteinuria of less than 0.5 g/day. We related these histopathological parameters with clinical data at biopsy and also with follow-up data. The percentage of glomeruli showing global sclerosis exceeded 10% of total glomeruli in 15 of the patients (39.5%) and exceeded 20% in 9 (23.7%). Arteriosclerosis and tubulointerstitial changes significantly correlated with glomerular sclerosis, but mesangial cell proliferation did not. Among the 38 patients, the 12 with hypertension showed more severe glomerular sclerosis, tubulointerstitial changes and arteriosclerosis compared with the 26 without hypertension, but the mesangial cell proliferation was identical between the two groups. Stepwise multiple regression analysis revealed that hypertension and urinary protein excretion (UPE) were independent risk factors for arteriosclerosis. The follow-up data of a mean period of 27.6 months showed that 9 of the 38 patients (23.7%) had an increase in UPE. Hypertension, arteriosclerosis, age, and UPE at biopsy were selected as the important risk factors for an increase in UPE in the follow-up. Our results provide not only clinical but histopathological evidence that hypertension affects the prognosis of mild proteinuric nephropathy through vascular lesions.

Adolescent↗

PubMedDate not supplied

Kidney function after left renal vein ligation in the dog.

The ligature of the left renal vein is an alternative whenever this vessel is injured. The purpose of this study was to evaluate the capacity of the affluents of the left renal vein, proximal to the ligature, to maintain tissue vitality and function of the left kidney. Fifteen mongrel male dogs were divided in 3 groups of 5 dogs: Group I (control) - a laparotomy was performed, and the abdominal structures were only identified; Group II - the left renal vein was tied, close to vena cava; Group III - the same procedure as for Group II and a right nephrectomy. Blood urea nitrogen and serum creatinine levels were measured before the procedure, and every 3 days during 4 weeks in the postoperative period. Renal arteriography and an excretory urogram were performed on the animals that survived 60 days. Thereafter, or immediately after precocious death, the kidneys were removed for histological examination. All the animals of Group III died before two months (mean = 10.5 +-3.2 days), while the animals of Group II survived during that period. There was a complete exclusion of the left kidney in all dogs that underwent renal vein ligature. In the animals of Group II, the renal cortico-medullary limits could not be identified. At microscopy, the aspect was suggestive of nephrosclerosis. In the animals of Group III, the left kidney was enlarged, and a great amount of intravascular and intrapelvic blood clots were observed. At microscopy, extensive areas of necrosis, inflammatory infiltration, and hemorrhage were identified. In conclusion, the tributaries of the renal vein were not sufficient to maintain the tissue vitality and function of the left kidney after ligature of its main vein.

Animals↗

PubMed2006

Renal involvement in leprosy: retrospective analysis of 461 cases in Brazil.

BACKGROUND: Renal lesions in leprosy have been extensively described, including amyloidosis, glomerulonephritis, nephrosclerosis, tubulointerstitial nephritis and granulomas. MATERIAL AND METHODS: A retrospective study was designed to detect renal function abnormalities in 461 leprosy patients, without any co-morbidity, seen in a university hospital in northeast Brazil. The laboratory test results concerning renal function were examined in the patients' medical records. RESULTS: The mean age was 39 +/- 18 years and 217 (47%) were male. The mean duration of disease was 21 +/- 38 months. Levels of creatinine above 1.4 mg/dL had been detected in 40 patients (8.6%). The levels of creatinine and urea were higher in lepromatous leprosy patients. Proteinuria, hematuria and hemoglobinuria were significantly more frequent in this presentation of leprosy. Nephrotic levels of proteinuria (>3.5 mg/dL) were found in three (2.1%) of 138 lepromatous leprosy patients. A positive association was found between duration of disease and high levels of creatinine in the general sample and in the lepromatous leprosy patients. There was no association between time of treatment and high levels of creatinine. CONCLUSION: Renal involvement in leprosy seems to be related to the quantity of bacilli present in the body. It is important to evaluate the renal function in all leprosy patients in order to detect any abnormality and prevent renal failure, which is still a potential cause of death in this disease.

Adolescent↗

PubMed2005

Y-box protein 1 mediates PDGF-B effects in mesangioproliferative glomerular disease.

The pivotal role of PDGF-B for mesangioproliferative glomerular disease is well established. Here, Y-box protein-1 (YB-1) was identified as a downstream signaling target of PDGF-B. In healthy kidney cells, YB-1 was located predominantly within the nuclear compartment. Subsequent to PDGF-B infusion and in the course of anti-Thy1.1-induced mesangioproliferative glomerulonephritis, relocalization of YB-1 into the cytoplasm was observed. In experimental models that lack profound mesangial cell proliferation (e.g., Puromycin-nephrosis, passive Heyman nephritis, spontaneous normotensive nephrosclerosis, hyperlipidemic diabetic nephropathy), YB-1 remained nuclear. This translocation coincided with upregulation of YB-1 protein levels within the mesangial compartment. Increased YB-1 expression and subcellular shuttling was dependent on PDGF-B signaling via the mitogen-activated protein kinase pathway because these alterations were prevented by specific PDGF aptamers and the mitogen-activated protein kinase pathway inhibitor U0126. Furthermore, PDGF-B strongly induced YB-1 expression in vitro. This induction was important because RNAi-dependent knockdown of YB-1 abolished the mitogenic PDGF-B effect. Taken together, YB-1 seems to represent a specific and necessary PDGF-B target in mesangioproliferative glomerular disease.

Animals↗