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

Previous studies have shown that the SA gene is expressed at higher levels in the kidney of genetically hypertensive rats than in control strains and that in hybrid crosses of genetically hypertensive rats and normotensive controls, markers in or close to the SA gene cosegregate with blood pressure. The present studies examine the localization of the SA gene product in the kidney by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). cDNA was prepared from microdissected nephron segments from Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHRs), and Wistar-Kyoto (WKY) rats, and RT-PCR was performed using specific primers. In all three strains, SA gene mRNA was found to be abundantly expressed in proximal tubules. SA PCR product was occasionally detected at approximately 100-fold lower abundance in glomeruli, while no signal was obtained from the collecting duct, thick ascending limb of the loop of Henle, or arcuate artery. Within the proximal tubule of normotensive rats, distribution of SA mRNA was found to be strain dependent: in SD rats it was expressed at high levels in the proximal convoluted tubule, whereas in WKY rats it was restricted to the proximal straight tubule. In SHRs, SA PCR product was detected along the entire proximal tubule. Induction of hypertension by renal artery clamping (two-kidney, one-clamp Goldblatt model) did not alter the pattern of expression observed in the SD rat. These results indicate that an extension of SA gene expression to the full length of the proximal tubule accompanies spontaneous hypertension and that in nonhypertensive animals the pattern of gene product expression is more restricted but shows substantial strain variability.
Hypertension 1996 Mar
PMID:SA gene expression in the proximal tubule of normotensive and hypertensive rats. 861

Recent studies have documented the presence of a complete renin-angiotensin system in the proximal tubule of the kidney: however, little is known about the regulation of renin in this proximal tubular system. Therefore, we performed the present studies to learn whether the behavior of the renin system in cultured proximal tubule is similar to that of the juxtaglomerular renin system. Basal renin secretion from rabbit proximal tubular cells in primary culture was low and not affected by isoproterenol (10(-5) mol/L), diltiazem (10(-5) mol/L), or a zero-calcium bath (O nmol/L). Only the calcium ionophore A23187 (10(-4) mol/L) significantly reduced renin secretion in these cells (from 2.44 +/- 0.37 to 1.14 +/- O.08 ng angiotensin I/mg protein per hour, P<.05). When the proximal tubular cells were lysed so the effects of the test agents on intracellular renin content could be assessed, isoproterenol caused a significant twofold (107 percent) increase (from 2.02 +/- 0.56 to 4.18 +/- 0.81 ng angiotensin I/mg protein per hour, P<.05), whereas diltiazem, A23187, and zero- and high-calcium baths did not produce a significant change. The effects of these agents on renin mRNA were examined in rabbit and rat proximal tubular cells in primary culture with the use of an S1 nuclease protection assay. Densitometry analysis of renin mRNA and either GAPDH mRNA (rat) or alpha-actin (rabbit) showed no significant alterations in renin mRNA abundance. In summary, these results confirm the presence of renin mRNA in cultured proximal tubular cells and suggest that a low-level, constitutive secretion of renin occurs in this system that is decreased by A23187. Moreover, the results also suggest that proximal tubular renin is regulated, albeit differently from the juxtaglomerular renin system. Finally, short-term increments in proximal tubular renin occur without a change in renin mRNA.
Hypertension 1996 Jun
PMID:Renin regulation in cultured proximal tubular cells. 864 45

Dopamine produced by renal proximal tubules acts as an intrarenal natriuretic factor by direct tubular action; this paracrine effect is influenced by the state of sodium balance. Up to 60% of sodium excretion with volume (2%-10%) expansion may be mediated by D1-like receptors. The renal paracrine effect of dopamine is impaired in genetic hypertension; this is due to defects in renal dopamine production or transduction of the dopamine signal. The Dahl salt sensitive rat and the spontaneously hypertensive rat (SHR), which have normal renal dopamine production and expression of dopamine receptors, have a defect in the coupling of a D1-like receptor to G-protein/effector enzyme complex. A consequence of the defective D1-like receptor/effector enzyme coupling in SHR is a decreased ability of D1 agonists to inhibit Na+/H+ exchange and Na+/K+-ATPase activity. The defect is 1) genetic, since it precedes the onset of and cosegregates with the hypertension; 2) receptor specific, since it is not shared by other humoral agents; and 3) confined to the renal proximal tubule. Two of the cloned dopamine receptors in mammals are D1-like (D1A and D1B). The D1A receptor gene is expressed to a greater extent in renal proximal tubules than the D1B receptor gene. The D1-like receptor is important in the pathogenesis of hypertension. Chronic blockade of dopamine receptors accelerates the development of hypertension in normotensive and hypertensive rats. Moreover, disruption of the D1A receptor gene in mice increases systolic blood pressure and results in diastolic hypertension. The abnormal D1-like receptor in SHR may be the D1A receptor; its uncoupling from the G-protein/effector enzyme complex in renal proximal tubules of SHR may be due to mistargeting. The mechanism for this "mistargeting" of the D1A receptor is not due to a mutation in the primary sequence and remains to be determined.
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PMID:Dopamine receptor signaling defects in spontaneous hypertension. 872 44

Acute arterial hypertension provokes a rapid decrease in proximal tubule (PT) Na+ reabsorption, increasing flow to the macula densa, the signal for tubuloglomerular feedback. We tested the hypothesis, in rats, that Na+ transport is decreased due to rapid redistribution of apical Na+/H+ exchangers and basolateral Na+ pumps to internal membranes. Arterial pressure was increased 50 mmHg by constricting various arteries. We also tested whether transporter internalization occurred when PT Na+ reabsorption was inhibited with the carbonic anhydrase inhibitor benzolamide. Five minutes after initiating either natriuretic stimuli, cortex was removed, and membranes were fractionated by density gradient centrifugation. Urine output and endogenous lithium clearance increased threefold in response to either stimuli. Acute hypertension provoked a redistribution of apical Na+/H+ exchanger NHE3, alkaline phosphatase, and dipeptidyl peptidase IV to higher density membranes enriched in the intracellular membrane markers. Basolateral membrane Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity decreased 50%, 25-30% of the alpha 1-and beta 1-subunits redistributed to higher density membranes, and the remainder is attributed to decreased activity of the transporters. Benzolamide did not alter Na+ transporter activity or distribution, implying that decreasing apical Na+ uptake does not initiate redistribution or inhibition of basolateral Na(+)-K(+)-ATPase. We conclude that PT natriuresis provoked by acute arterial pressure is mediated by both endocytic removal of apical Na+/H+ exchangers and basolateral Na+ pumps as well as decreased total Na+ pump activity.
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PMID:Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis. 876 20

Interleukin 6 (IL-6) is produced by human mesangial and tubular cells, and its urinary levels has been proposed as a marker of mesangial proliferation and tubulointerstitial damage. Epidermal growth factor (EGF) is expressed within the Henle's loop and the distal tubule and has been shown to accelerate recovery from renal injury. In the present study we have defined renal gene and protein expression of IL-6 and EGF in 10 normal, 10 nonproliferative glomerulonephritis (NPGN) and 30 IgA nephropathy (IgAN) human kidneys by RT-PCR, in situ hybridization and immunohistochemical techniques. Moreover, urinary IL-6 and EGF levels were measured in 41 patients with IgAN and in 20 normal subjects (N). In normal kidneys, EGF was localized in Henle's loop and distal convoluted tubule whereas IL-6 was mainly located in the proximal tubule and, less, within the glomerulus. In IgAN patients, EGF was decreased whereas IL-6 expression was upregulated. These modifications paralleled the degree of tubulointerstitial damage. Moreover, IgAN patients as a whole exhibited a reduction of EGF and an increase of IL-6 urinary concentration (EGF values: N, 12.96 +/- 1.15; IgAN Grades 1-2, 20.05 +/- 2.64; Grades 3-4 7.60 +/- 1.70: Grade 5, 3.14 +/- 0.71, ng/mg urinary creatinine. IL-6 values: N, 2.04 +/- 0.51; IgAN Grades 1-2, 3.26 +/- 0.38; Grades 3-4, 5.67 +/- 0.92; Grade 5, 27.20 +/- 9.70 pg/mg urinary creatinine), that correlated with the degree of histological lesions, the presence of hypertension and serum creatinine level. Interestingly, patients with the highest urinary IL-6/EGF ratio showed a worse evolution in a three year follow-up. In conclusion, our data show that: (1) renal IL-6 and EGF expression are strictly correlated to the degree of tubulointerstitial damage; and (2) urinary IL-6/EGF ratio might be a valuable prognostic marker for the progression of the renal damage in IgAN.
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PMID:Urinary IL-6/EGF ratio: a useful prognostic marker for the progression of renal damage in IgA nephropathy. 894 82

Dopamine (DA) produces a natriuresis attributed in part to inhibition of Na,K-ATPase activity (NKA) in the proximal tubule (PCT), and impairment in this inhibition has been linked to several forms of hypertension in animals. Here we examined whether the intracellular signaling mechanisms involved are the same in the early and late phases of this phenomenon. DA (1 microM) inhibited NKA similarly after 15 min (by 38%) or 180 min (by 36%) incubation, taken to represent short-term (ST) and sustained (Sd) pump regulation, respectively. Calphostin C, a specific inhibitor of protein kinase C (PKC), completely blocked the ST action of DA on NKA, whereas IP20, a specific inhibitor of protein kinase (PKA), had no effect. In contrast, IP20 completely abolished the Sd (180 min) inhibition by DA, whereas calphostin C had only a partial or variable effect. The DA-1 agonist fenoldopam (which does not activate PKC but increases cAMP) alone failed to inhibit the pump at 180 min (as it does also in the short-term in PCT), suggesting that ST inhibition is required for the Sd effect to occur. Furthermore, PTH1-34, a known ST inhibitor of NKA suppressed the pump at 180 min (by 46%), but unlike in the short-term, this effect was completely prevented by IP20. In contrast, PTH3-34, which does not stimulate adenylyl cyclase or activate PKA, caused only a small (19%) and variable Sd inhibition. In conclusion, short-term inhibition of the PCT pump by dopamine is mediated via PKC, whereas the sustained inhibition requires the PKA pathway in addition to the ongoing PKC-mediated effect.
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PMID:Short-term vs. sustained inhibition of proximal tubule Na,K-ATPase activity by dopamine: cellular mechanisms. 902 36

1. The renal effects of insulin may play a central role in the association between insulin resistance, hypertension and hyperuricaemia. After a 2-h baseline period, we investigated the effects of exogenous insulin for 4 h (50 m-units h-1 kg-1) on fractional renal sodium and urate excretion in 13 healthy subjects, using the euglycaemic clamp and lithium clearance technique, and performed a control experiment in eight of the subjects. 2. Insulin caused a decline in both fractional renal sodium excretion, from 1.13 +/- 0.41% to 0.88 +/- 0.58% (control study: 0.81 +/- 0.35 to 1.35 +/- 0.49%; P < 0.001, insulin versus control), and fractional renal urate excretion, from 6.72 +/- 1.87% to 5.71 +/- 2.02% (control study: 7.03 +/- 2.06 to 7.05 +/- 1.94%; P = 0.085, insulin versus control). The changes in fractional renal sodium and urate excretion were positively correlated (r = 0.71, P < 0.01). Estimated fractional distal sodium reabsorption increased during insulin infusion from 93.7 +/- 2.8% to 96.7 +/- 1.9% (control study: 95.7 +/- 1.5% to 93.6 +/- 1.1%; P < 0.001, insulin versus control). Estimated fractional proximal tubular sodium reabsorption fell from 81.0 +/- 0.5% to 73.7 +/- 4.7% during insulin infusion, but less in the control study (81.5 +/- 4.3% to 79.3 +/- 4.8%; P = 0.056, insulin versus control). The changes in fractional proximal tubular sodium reabsorption and fractional distal sodium reabsorption during insulin infusion were inversely correlated (r = -0.59, P = 0.03). 3. During the course of the insulin infusion experiment an inverse correlation between the changes in fractional sodium and urate excretion, and the insulin-mediated glucose disposal, became gradually evident (r = -0.73, P < 0.01, and r = -0.71, P < 0.01, respectively; fourth hour of the insulin infusion period). 4. We conclude that exogenous insulin acutely decreases renal sodium and urate excretion, and that this effect is probably exerted at a site beyond the proximal tubule.
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PMID:Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. 903 91

In autoradiographic studies in anesthetized rats, 125I-labeled amylin binding was associated with proximal convoluted tubules but not distal tubules, interstitium, or glomeruli in the renal cortex. Split-drop micropuncture experiments showed that perfusion of the peritubular capillaries with amylin (10(-9) M) stimulated proximal tubular fluid absorption by 28%. This effect was inhibited by luminal addition of ethylisopropylamiloride, indicating mediation by a brush-border Na+/H+ exchanger. Intravenous infusion of an amylin binding antagonist, AC-187, reduced proximal fluid reabsorption (22%) in anesthetized rats, indicating a role for endogenous amylin in salt homeostasis. In primary cultures of rat proximal tubule cells, amylin (10(-7) M) stimulated proliferation with a potency equal to epidermal growth factor. Peptide antagonists (AC-187, AC-413, and AC-512) of the amylin binding sites in the renal cortex blocked the mitogenic action of amylin. We conclude that amylin acts on renal proximal tubules to promote sodium and water reabsorption and cell proliferation. These novel actions may have implications for the development of hypertension for example in non-insulin-dependent diabetes mellitus and obesity in which hyperamylinemia has been observed.
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PMID:Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney. 903 44

Dopamine (DA), produced by the renal proximal tubule, has been demonstrated as an intrarenal paracrine hormone mediating diuresis and natriuresis. The precise mechanism by which DA exerts its cell-to-cell action is not fully understood. In the present study, renal interstitial fluid (RIF) DA (by in vivo microdialysis) and urinary DA excretion (UDAV) were compared in anesthetized rats on either normal (0.28% NaCI, NS) or high (4.0% NaCI, HS) sodium balance and in response to acute gamma-L-glutamyl-L-dopa (gludopa) administration. Urine flow (UV) and sodium excretion (UNaV) in HS were greater than in NS rats. UDAV was increased in HS compared with NS rats. RIF DA was significantly lower in HS than NS rats. Gludopa at 3, 5, and 7.5 nmol/kg (IV bolus) produced a larger increase in UDAV than RIF DA. Only the highest dose of gludopa (7.5 nmol/kg), which resulted in a 7.3-fold increase in UDAV and 1.7-fold increase in RIF DA, was associated with significant diuresis and natriuresis. Cortical and medullary blood flow remained unchanged after gludopa (7.5 nmol/kg) administration, while angiotensin II (100 ng.kg-1.min-1) induced significant reduction in cortical and medullary blood flow. Prior bilateral renal denervation did not have a significant effect on basal DA levels (RIF DA and UDAV) or gludopa-induced DA production or natriuresis and diuresis. These data demonstrated that both chronic sodium loading and acute gludopa administration stimulated renal DA production and release predominantly into the tubule lumen, where DA had a direct tubule action in the control of UNaV. Renal DA production and its renal effects were not significantly regulated by renal sympathetic nerve activity.
Hypertension 1997 Jan
PMID:Intrarenal dopamine production and distribution in the rat. Physiological control of sodium excretion. 903 7

Increased activity of the cellular Na(+)-H+ exchangers (NHEs), especially isoform 1 (NHE-1), is a recognized intermediate phenotype of hypertension. NHE activity has been demonstrated to be increased in proximal tubules of the spontaneously hypertensive rat (SHR). However, with the recent cloning of other members of this family of transporters, it is unclear which isoforms may contribute to this increased activity. We have used specific antibodies raised against glutathione-S-transferase fusion proteins of rat NHE-1 and NHE-3 to determine the relative contributions of these isoforms to the NHE activity in freshly isolated and cultured proximal tubule cells from SHR and Wistar-Kyoto (WKY) normotensive control rats. In freshly isolated proximal tubule cells, NHE activity was elevated almost 3-fold in SHR cells (P < .001), and in both rat strains, the contribution from NHE-1 and NHE-3 was approximately equal. Western blots of membranes from these cells showed equal amounts of NHE-1 protein in SHR and WKY cells. However, NHE-3 protein expression was increased 50% in SHR cells (P < .001), and this may account for the elevated activity of this isoform in SHR. The effect of culturing these cells in vitro was then examined. Although total NHE activity in both cell types was decreased during culture, this was mainly due to loss of expression of NHE-3 protein. NHE-1 activity was persistently elevated in the SHR cells in culture. These findings suggest that elevated NHE activity in SHR proximal tubules could be mediated by two mechanisms: (1) increased NHE-1 activity without any increased NHE-1 protein content that persists despite culture and may resemble those changes described for extrarenal tissues and (2) increased NHE-3 activity due to increased expression of NHE-3 protein. Disappearance of NHE-3 during culture implies that our culture conditions did not replicate the in vivo environment and may have removed the factors contributing to the increased NHE-3 expression in SHR cells.
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PMID:Activity and expression of Na(+)-H+ exchanger isoforms 1 and 3 in kidney proximal tubules of hypertensive rats. 916 88


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