Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent proteinuria is considered a deleterious prognostic factor in most progressive renal diseases. However, the mechanisms by which proteinuria induces renal damage remain undetermined. Since proximal tubular cells possess all the machinery to generate angiotensin II (Ang II), we approached the hypothesis that proteinuria could elicit the renal activation of the renin-angiotensin system in a model of intense proteinuria and interstitial nephritis induced by protein overload. After uninephrectomy (UNX), Wistar-Kyoto rats received daily injections of 1 g BSA or saline for 8 days. The mean peak of proteinuria was observed at the fourth day (538+/-89 versus 3+/-1 mg/24 h in UNX controls; n=12; P<0.05) and was increased during the whole study period (at the eighth day: 438+/-49 mg/24 h; n=12; P=NS). Morphological examination of the kidneys at the end of the study showed marked tubular lesions (atrophy, vacuolization, dilation, and casts), interstitial infiltration of mononuclear cells, and mesangial expansion. In relation to UNX control rats, renal cortex of BSA-overloaded rats showed an increment in the gene expression of angiotensinogen (2.4-fold) and angiotensin-converting enzyme (ACE) (2.1-fold), as well as a diminution in renin gene expression. No changes were observed in angiotensin type 1 (AT1) receptor mRNA expression in both groups of rats. By in situ reverse transcription-polymerase chain reaction and immunohistochemistry, ACE expression (gene and protein) was mainly localized in proximal and distal tubules and in the glomeruli. By immunohistochemistry, angiotensinogen was localized only in proximal tubules, and AT1 receptor was localized mainly in proximal and distal tubules. In the tubular brush border, an increase in ACE activity was also seen (5. 5+/-0.5 versus 3.1+/-0.7 U/mg protein x10(-4) in UNX control; n=7; P<0.05). Our results show that in the kidney of rats with intense proteinuria, ACE and angiotensinogen were upregulated, while gene expression of renin was inhibited and AT1 was unmodified. On the whole, these data suggest an increase in Ang II intrarenal generation. Since Ang II can elicit renal cell growth and matrix production through the activation of AT1 receptor, this peptide may be responsible for the tubulointerstitial lesions occurring in this model. These results suggest a novel mechanism by which proteinuria may participate in the progression of renal diseases.
Hypertension 1999 Feb
PMID:Angiotensin-converting enzyme is upregulated in the proximal tubules of rats with intense proteinuria. 1002 37

To demonstrate potential therapeutic effects of kallikrein gene delivery in salt-induced hypertension and renal diseases, we delivered adenovirus carrying the human tissue kallikrein gene (Ad.CMV-cHK) into deoxycorticosterone acetate (DOCA)-salt hypertensive rats. A single intravenous injection of Ad.CMV-cHK caused a delay in the rise of blood pressure that began 2 days post gene delivery and lasted for more than 23 days. A maximal blood pressure reduction of 50 mm Hg was observed in rats receiving kallikrein gene delivery, as compared to rats receiving adenovirus containing the luciferase gene (Ad.CMV-Luc) (172 +/- 5 vs. 222 +/- 13 mm Hg, n = 6, P < 0.01). Throughout the experimental period, a blood pressure reduction of at least 32 mm Hg was observed in the DOCA-salt rats injected with Ad.CMV-cHK as compared to DOCA-salt rats receiving control adenovirus. Immunoreactive human tissue kallikrein levels were detected in rat serum and urine post gene delivery. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in urinary excretion, urinary protein levels and body weight. Morphological examination of the kidney showed that kallikrein gene transfer significantly reduced DOCA-salt-induced glomerular sclerotic lesions, brush border disruption of proximal tubules, tubular dilatation and protein cast accumulation. These findings showed that the expression of human tissue kallikrein via gene delivery has protective effects against hypertension and renal injury in DOCA-salt hypertensive rats.
 ...
PMID:Adenovirus-mediated kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxycorticosterone-salt rats. 1060 25

Acute hypertension provokes a rapid decrease in proximal tubule salt and water reabsorption that increases the levels of sodium chloride at the macula densa, the error signal to increase arteriolar resistance to autoregulate renal blood flow and glomerular filtration rate, and contributes to pressure natriuresis. The molecular mechanisms responsible for this critical homeostatic adjustment are beginning to be dissected: apical sodium transporters in the proximal tubule are redistributed out of the brush border to intermicrovillar and endosomal stores and sodium pump activity is inhibited. These responses are strikingly similar to the cellular responses to parathyroid hormone, and are mediated by similar signalling pathways.
 ...
PMID:Molecular mechanisms of sodium transport inhibition in proximal tubule during acute hypertension. 1075 20

Acute hypertension in Sprague-Dawley rats (SD) provokes a decrease in renal proximal tubule (PT) salt and fluid reabsorption, redistribution of apical Na/H exchanger isoform 3 (NHE3) and Na-P(i) cotransporter type 2 (NaPi2) out of the brush border into higher density membranes, and inhibition of renal cortical Na-K-ATPase (NKA) activity (41). The aims of this study were to determine 1) whether an increase in arterial pressure affects distribution or activity of Na transporters in the spontaneously hypertensive rat (SHR) and 2) whether development of chronic hypertension in SHR leads to persistent adaptive changes in NHE3 and NaPi2 distribution and/or NKA activity. Renal cortex Na transporter protein density distributions and activities were compared by subcellular fractionation in 1) adult SHR with an acute increase or decrease in arterial pressure and 2) young SD (YSD) and young SHR (YSHR) vs. adult SD and SHR. In adult hypertensive SHR NHE3 was shifted to membranes of higher densities, analogous to SD with acute hypertension, and there were no further changes with a further increase or decrease in arterial pressure. There was no change in total pool size of NHE3 in cortex in YSHR vs. SHR. NHE3, NaPi2, megalin, NKA alpha-/beta-subunit, dipeptidyl peptidase IV (DPPIV), and villin distributions were the same in YSHR vs. YSD. NHE3, NaPi2, and megalin shifted to higher densities in adult SHR, but not SD, with age. Basolateral NKA and apical alkaline phosphatase activities were 40% greater in YSHR than YSD and decreased to SD levels in adults. We conclude that there are persistent changes in Na(+) transporter distributions and activity in response to chronic hypertension in SHR that mimic the responses to acute hypertension seen in SD rats and that elevated sodium pump activity per transporter in YSHR may contribute to the generation of hypertension.
 ...
PMID:Proximal tubule Na transporter responses are the same during acute and chronic hypertension. 1091 57

The ability of dopamine(1) (D(1)) receptors to inhibit luminal Na(+)-H(+) exchanger (NHE) activity in renal proximal tubules and induce a natriuresis is impaired in spontaneously hypertensive rats (SHR). However, it is not clear whether the defect is at the level of the D(1) receptor, G(salpha), or effector proteins. The coupling of the D(1) receptor to G(salpha) and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D(1) receptor, G(salpha), and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5'-O:-(3-thiotriphosphate) (GTPgammaS) decreased NHE activity and increased NHE3 linked with G(salpha) similarly in WKY and SHR, indicating normal G(salpha) and NHE3 regulation in SHR. However, D(1) agonists increased NHE3 linked with G(salpha) in WKY but not in SHR, and the inhibitory effects of D(1) agonists on NHE activity were less in SHR than in WKY. Moreover, GTPgammaS enhanced the inhibitory effect of D(1) agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D(1) receptor from G(salpha)/NHE3 in SHR. Similar results were obtained with the use of immortalized renal proximal tubule cells from WKY and SHR. We conclude that the defective D(1) receptor function in renal proximal tubules in SHR is proximal to G(salpha)/effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D(1) receptor from G proteins remains to be determined. Because the primary structure of the D(1) receptor is not different between normotensive and hypertensive rats, differences in D(1) receptor posttranslational modification are possible.
Hypertension 2000 Sep
PMID:Dopamine(1) receptor, G(salpha), and Na(+)-H(+) exchanger interactions in the kidney in hypertension. 1098 71

We previously showed that acute arterial hypertension induces an inhibition of fluid and NaCl reabsorption in proximal tubules of Sprague-Dawley rats, which is associated with a rapid reversible internalization of apical Na(+)/H(+) exchanger in brush border. To determine whether there is a corresponding inhibition of apical Na(+)/H(+) exchanger activity in proximal tubules to account for the reduced tubular reabsorption, an instrument capable of measuring intracellular pH (pH(i)) ratiometrically and repeatedly on the surface of kidney with high temporal resolution is required. We report the design and validation of such a fluorimetric system based on two ultraviolet nitrogen-pulsed lasers and a photomultiplier. pH(i) of proximal tubules in situ was measured with pH-sensitive fluorescence dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein at 5 Hz. Using the initial rate of change of pH(i) (dpH(i)/dt) during luminal Na(+) removal as an index of apical Na(+)/H(+) exchanger activity, the exchanger activity was found to be reduced by 52 +/- 11% (n = 14, P < 0.05) compared with the baseline after 20 min of induced acute hypertension. The inhibition of Na(+)/H(+) exchange activity was alleviated when the blood pressure was returned to prehypertensive level. These observations indicate that acute changes in arterial pressure can reversibly inhibit apical Na(+)/H(+) exchanger activity, which might contribute to pressure natriuresis in proximal tubule.
 ...
PMID:Detection of apical Na(+)/H(+) exchanger activity inhibition in proximal tubules induced by acute hypertension. 1100 11

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloon-injured carotid arteries and induces marked vascular and tubulointerstitial injury in kidneys. We examined how the AT1 receptor is modulated and whether blockade of the receptor with losartan could prevent the phenotypic and cellular changes. We also examined the role of the local renin-angiotensin system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and medial thickening in balloon-injured carotid arteries. Renal injury was manifested by proteinuria, glomerular phenotypic changes (mesangial expression of alpha-actin and podocyte expression of desmin), and tubulointerstitial injury with the tubular upregulation of the macrophage-adhesive protein, osteopontin, the interstitial accumulation of macrophages and myofibroblasts, and the deposition of collagen types III and IV. Ang II infusion decreased AT1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and injury to both carotid and kidney. Ang II infusion was also associated with an increase in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies demonstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activation, the injury appears to be mediated solely by the exogenous Ang II.
 ...
PMID:Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent. 1117 28

Dopamine via the activation of D1-like receptors inhibits Na,K-ATPase and Na,H-exchanger and subsequently increases sodium excretion. We have previously reported that dopamine failed to inhibit Na,K-ATPase in the proximal tubules (PTs) of obese Zucker rats. The present study was designed to determine the effect of dopamine on Na,H-exchanger in PTs of lean and obese Zucker rats, and examine D1-like receptor-coupled signal transduction pathway mediating the inhibition of Na,H-exchanger. We found that dopamine inhibited Na,H-exchanger in the PTs of lean rats but this response was absent in obese rats. In brush border membranes, [3H]SCH 23390 binding revealed a approximately 45% reduction in D1-like receptor binding sites in obese compared to lean rats. Dopamine stimulated cAMP accumulation in PTs of lean but not in obese rats. Forskolin-mediated stimulation of cAMP was similar in lean and obese rats. Dopamine as well as forskolin and dibutyryl cAMP-mediated stimulation of protein kinase A (PKA) was reduced in PTs of obese compared to lean rats. The data suggest that reduction in D1-like receptor binding sites, defective coupling with signaling pathway and inability of PKA activation may be responsible for the failure of dopamine to inhibit Na,H-exchanger in PTs of obese rats. This phenomenon may contribute to an increase in sodium reabsorption and development of hypertension in obese Zucker rats.
 ...
PMID:Dopamine fails to inhibit Na,H-exchanger in proximal tubules of obese Zucker rats. 1172 4

Acute hypertension rapidly decreases proximal tubule (PT) Na(+) reabsorption, facilitated by a redistribution of PT Na(+)/H(+) exchangers (NHE3) out of the apical brush border, increasing NaCl at the macula densa, the signal for autoregulation of renal blood flow and GFR. This study aimed to determine whether NHE3 activity per transporter decreases during acute hypertension and the time dependence of the response. Blood pressure was elevated by 50-60 mmHg in male Sprague-Dawley rats for 5 or 30 min by constricting arteries. Renal cortical membranes were fractionated by density gradient centrifugation. NHE3 transport activity was assayed as the rate of appearance of acridine orange (AO) from AO-loaded vesicles in response to an inwardly directed Na(+) gradient. After 5-min hypertension, 20% of total NHE3 protein, assayed by immunoblot, redistributed from low-density apical membranes to middensity membranes enriched in intermicrovillar cleft markers; by 30 min, a similar percentage shifted to heavier density membranes containing markers of endosomes. NHE3 activity shifted to higher density membranes along with NHE3 protein, that is, no change in activity/transporter during acute hypertension. Confocal analysis of NHE3 distribution also verified removal from apical microvilli and appearance in subapical vesicles. We conclude that the decrease in renal PT Na(+) transport during acute hypertension is mediated by removal of transport-competent NHE3 from the apical brush border to subapical and internal reserves.
 ...
PMID:Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. 1188 Mar 35

Impairment of kidney function in various types of glomerular disease is associated with tubulointerstitial changes. Monocyte chemoattractant protein-1 (MCP-1) is up-regulated in the tubulointerstitium and in the glomeruli in many human and experimental kidney disorders. We investigated the localization of MCP-1 expression in a rat model of progressive kidney failure. Male Wistar rats were subjected to subtotal nephrectomy (n = 30) or sham surgery (n = 30). Immunohistochemistry with immunoelectron microscopy and in situ hybridization were used to examine the expression of MCP-1 protein and messenger ribonucleic acid (mRNA) in the kidney, respectively. MCP-1 protein and mRNA were hardly detected in both glomeruli and tubulointerstitium of control rats. However, in the rats subjected to nephrectomy, MCP-1 expression was increased in the tubular cells of the remnant kidney, accompanied by significant macrophage infiltration. MCP-1 was observed mainly in the proximal tubular cells and only weakly in distal tubular cells. No significant expression of MCP-1 protein or mRNA was noted in the glomeruli. Immunoelectron microscopy showed the presence of MCP-1 in the rough endoplasmic reticulum of proximal tubular cells, confirming that MCP-1 is produced in proximal tubular cells. MCP-1 was also observed in endocytic vesicles adjacent to the brush border of proximal tubular cells, suggesting incorporation of MCP-1 from the tubular lumen. Our findings indicate localized expression of MCP-1 in proximal tubular cells in the remnant kidney and suggest that MCP-1 in proximal tubular cells is involved in tubulointerstitial damage in chronic kidney failure associated with glomerular hypertension.
 ...
PMID:Expression of monocyte chemoattractant protein-1 in proximal tubular epithelial cells in a rat model of progressive kidney failure. 1208 Mar 27


<< Previous 1 2 3 4 5 6 7 8 Next >>