Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q92565 (GFR)
 4,179 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A growing body of evidence supports the notion that calcium antagonists exert a renal protective effect. Calcium antagonists may play an important future role in renal hemodynamics related to their reversal of renal vasoconstrictors. Calcium antagonists are also capable of blocking intracellular calcium overload induced by various types of ischemia or toxic stimuli. Features such as these may be of substantial value in ameliorating acute renal insufficiency secondary to renal ischemia, iodinated radiographic contrast media, or the administration of various nephrotoxic drugs. The latter includes agents such as the aminoglycoside antibiotics, cyclosporine A, and the cancer chemotherapeutic agent cisplatin. Recent prospective, controlled studies from our group indicate that calcium antagonists protected against postischemic acute renal failure in the setting of cadaveric renal transplantation. Moreover, in a prospective, randomized, controlled clinical trial, we were able to demonstrate that the prophylactic use of nitrendipine reduced the decrease in GFR in patients receiving radiographic contrast agents. Such protection may extend to favorably influencing the course of chronic renal insufficiency, particularly when the latter is complicated by hypertension. Seven putative mechanisms have been proposed by which calcium antagonists may ameliorate the decline in GFR associated with renal insufficiency. These are: (a) reduction in blood pressure per se, (b) reduction in renal hypertrophy, (c) modulation of mesangial traffic of macromolecules, (d) reduction in metabolic activity in remnant renal tissue, (e) amelioration of uremic nephrocalcinosis, (f) reduction of pressure-induced calcium entry into vessel walls, and (g) reduction of free radical formation. Experimental investigations in rats with reduced renal mass, desoxycorticosterone-induced hypertension, or chronic angiotensin II infusion, and in spontaneously hypertensive rats support such a view.
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PMID:Calcium antagonists and renal protection. 851 90

F2-isoprostanes are the newly identified reactive oxygen species-catalyzed peroxidation products of arachidonate. The infusion of these prostaglandin F2-like prostanaoids into the rat kidney induces profound parallel reductions in RBF and GFR, suggesting that these metabolites may be partly responsible for the hemodynamic alterations seen in free radical-linked acute renal injury models. The present study examined directly in renal proximal tubular (LLC-PK1) cells whether hydrogen peroxide, a reactive oxygen species implicated in many models of acute renal injury, induces F2-isoprostane production and whether its production can be inhibited by the recently synthesized lipid peroxidation inhibitor 21-aminosteroid (lazaroid U-74389G). The incubation of LLC-PK1 cell layers with hydrogen peroxide for 3 h resulted in a dose-related six-fold increase in F2-isoprostane production, measured by the gas chromatographic-mass spectroscopic method. The preincubation of cells with 21-aminosteroid prevented hydrogen peroxide-induced F2-isoprostane production, a finding also demonstrable with other lipid peroxidation inhibitors, e.g., 2-methyl aminochroman (U-83836E) and diphenyl-p-phenylenediamine. Besides inhibiting isoprostane production, 21-aminosteroid reduced hydrogen peroxide-induced lipid degradation and peroxidation, and protected the cells against hydrogen peroxide-induced cytolysis. The novel finding that hydrogen peroxide induces 21-aminosteroid-inhibitable F2-isoprostane production in renal epithelial cells supports the in vivo report that its levels are elevated in reactive oxygen species-linked renal injury models such as ischemia-reperfusion. Besides direct cell injury, lipid peroxidation by generating F2-isoprostanes may further contribute to renal dysfunction through a vasoconstrictive mechanism. Thus, the inhibition of excess F2-isoprostane production may be one of the additional mechanisms, besides cytoprotection, by which antioxidants ameliorate renal dysfunction in experimental models of acute renal injury.
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PMID:Hydrogen peroxide induces 21-aminosteroid-inhibitable F2-isoprostane production and cytolysis in renal tubular epithelial cells. 858 1

Adenosine infusion is associated with natriuresis as well as antinatriuresis. The physiologic significance of these opposite effects is unknown but may have to do with different conditions of ischemia, in which adenosine accumulates. These effects were characterized in the rat. First, intrarenal and systemic infusions within one animal were performed. Infusing 10 micrograms/min into the left renal artery increased sodium by approximately 50%; however, the subsequent infusion of 50 micrograms/min into the thoracic aorta decreased sodium excretion by approximately 60%, in association with a small reduction of blood pressure. Second, to explore the effect of intrarenal adenosine in tubular sodium handling, free-flow micropuncture experiments were performed. The intrarenal infusion of 10 micrograms/min again caused sodium excretion, but no change in GFR, volume, and sodium deliveries up to the early distal tubule was found. Apparently, the direct effect of adenosine in the kidney is sodium excretion, by a tubular action beyond the early distal tubule. Third, to further characterize the indirect effect, which apparently is sodium retention, adenosine was infused systemically at low rates, in order to avoid a decrease in blood pressure. A 25 micrograms/min infusion again caused sodium retention, in the absence of a fall in blood pressure. After acute left renal denervation, the antinatriuretic effect disappeared in the denervated kidney but remained in the right kidney. These data suggest that increased intrarenal adenosine suppresses sodium reabsorption at some distal nephron site, appropriately decreasing the workload of the kidney. On the other hand, systemic adenosine stimulates sodium reabsorption, an effect that is appropriate to improve systemic circulation and depends on the renal nerves.
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PMID:Adenosine and renal sodium handling: direct natriuresis and renal nerve-mediated antinatriuresis. 858 28

This study evaluated the effect of systemic infusion of hypertonic mannitol on renal hemodynamics (aortic pressure [P]-renal blood flow [RBF] relationship, glomerular filtration rate [GFR], and effective renal plasma flow [ERPF]) during 50% reduction of left kidney blood flow. Conditioned mongrel dogs anesthetized with halothane were hydrated by continuous infusion of lactated Ringer's solution containing creatinine to measure GFR and p-aminohippurate (PAH), to measure ERPF. The left kidney was exposed and two hydraulic occluders were placed, one around the aorta just above the renal arteries and the other around the left renal artery. Experimental design consisted of measuring P near the left renal artery, RBF by electromagnetic flowmeter, and ERPF and GFR by clearance methods in both kidneys in response to stepwise reduction in the aortic pressure by aortic occlusion before and after 50% reduction in the left kidney blood flow. The P-RBF relationship, GFR, and ERPF thus obtained were compared with those obtained during systemic intravenous infusion of 20% mannitol for a period of 1 h. We found that 1) a transient increase occurred in RBF with step reduction of P from 80 to 60 mm Hg under control conditions; 2) reducing the RBF by 50% changed the shape of the P-RBF relationship from a convex to the P axis to a linear form with a marked shift toward the P axis; 3) infusion of mannitol, during reduced RBF, caused a significant shift of the P-RBF curve toward the RBF axis and returned the linear P-RBF relationship toward normal, but had no effect on altered yield pressure; and 4) infusion of hypertonic mannitol had slightly increased GFR and ERPF in the right (unconstricted) kidney. However, hypertonic mannitol significantly increased GFR and ERPF values in the left (constricted) kidney suggesting a beneficial effect of mannitol on ischemic kidney. The results are consistent with the hypothesis that infusion of hypertonic mannitol to ischemic kidney increases RBF, presumably by decreasing the intrarenal vascular resistance. We speculate that this compensatory response may be mediated either 1) by stimulating the release of a vasodilator substance (e.g., prostaglandins), or 2) by washing out interstitial sodium, thereby reducing the sensitivity of the renal vasculature to ischemia-induced stimulation of renin-angiotensin system.
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PMID:Effects of hyperosmotic mannitol infusion on hemodynamics of dog kidney. 861 Aug 95

The influence of ketanserin, a S2-serotonergic receptor blocker, on the impaired renal hemodynamics in a clamp model of renal ischemia in rats was investigated in this study. Serotonin-induced vasoconstriction of the renal vascular bed was augmented after ischemia. This constriction is blocked by ketanserin (0.05 mg/kg i.v. bolus, followed by 0.1 mg/kg per h infusion). The influence of the same ketanserin treatment on the response of RBF versus a stepwise lowering of the renal perfusion pressure was studied in post-ischemic kidneys with an established loss of autoregulation of RBF. An almost perfect restoration of the autoregulatory response was apparent after the S2-serotonergic antagonism. Despite this beneficial effect on renal hemodynamics, renal function, judged by measurement of GFR and urinary sodium excretion rate, was not influenced by an acute infusion of ketanserin in post-ischemic kidneys. It is suggested that serotonin plays a pivotal role in the suppression of autoregulation of RBF by a S2-serotonergic receptor-mediated vasoconstrictor effect in the post-ischemic kidney. It most likely masks the potential myogenic dilatory response of the smooth muscle cells in renal preglomerular microvasculature. Restoration of the renal autoregulatory capacity by S2-serotonergic receptor antagonism could be of clinical relevance in human post-ischemic acute renal failure.
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PMID:Beneficial influence of ketanserin on autoregulation of blood flow in post-ischemic kidneys. 872 97

Primary hyperoxaluria type 1 (PH 1) is complicated by a high rate of early end-stage renal failure (ESRF). In ESRF combined liver kidney transplantation has emerged as treatment of choice for teenagers and adults. In chronic renal failure (CRF) and for small children the situation is less clear. We report on three isolated liver transplantations and show the data of young children from the European Registry for liver transplantation in PH 1. Patient #1 developed ESRF at 3 months of age. Deficiency of alanine:glyoxylate aminotransferase proved PH 1. Progressive bone disease developed and the boy received a living related liver graft (LRLTx) at age two. Due to recurrent cholangitis kidney transplantation (KTx) is currently not feasible. Plasma oxalate decreased after LRLTx indicating correction of the metabolic defect. Patient #2 was diagnosed at the age of 14 months. He had nephrocalcinosis and hyperglycolic hyperoxaluria. Two years later he developed ESRF. At 5 years of age isolated liver transplantation was performed as a first step of therapy. Due to prolonged warm ischemia time organ function was poor. A severe bleeding complicated the course. The child died four weeks after transplantation from untreatable CMV septicemia. Patient #3 was evaluated for failure to thrive at 6 months of age. Urinary oxalate/creatinine ratio was 705 mumol/mol and gave rise to the diagnosis of PH 1. Renal failure slowly progressed to a creatinine clearance of 20 ml/min/1.73 m2 at 8 years, when liver transplantation (LTx) was performed. Four months later, GFR has not changed. Liver function and urinary oxalate/creatinine ratio are normal. Slowly deteriorating chronic renal failure can be stabilized through isolated liver transplantation and thus the rapid need for KTx will at least be delayed. Even more important, normalization of the oxalate metabolism prevents extrarenal oxalate deposits during renal failure.
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PMID:Transplantation procedures in primary hyperoxaluria type 1. 883 45

This study was carried out in order to examine whether the severity of acute renal failure observed during the four hours following a 45 min period of unilateral occlusion of the renal pedicle could be reduced by various treatments. These include intrarenal flush with saline immediately before the occlusion, by sucrose infusion immediately before reperfusion, or by injection of NAO (natural antioxidant) and vitamin E before the occlusion. After renal pedicle occlusion, creatinine levels increased to 165% of their pre-ischemic values. Urine flow, GFR, renal cortex blood flow and NADH decreased by 99%, 99%, 50% and 36%, respectively. A decrease in the Na and K reabsorption (15% and 32%, respectively) was also observed. Partial protection of renal function against ischemic damage was observed when kidney tissue remained blood-free, by exposing it to saline throughout the period of ischemia. Significant protection was observed after treatment with sucrose, vitamin E and NAO. This study demonstrates that it is possible to attenuate the injury to the ischemic kidney by inducing ischemia in a bloodless kidney, by inducing diuresis in the first phase of reperfusion, or by antioxidant treatment, such as vitamin E or NAO.
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PMID:Unilateral renal ischemia reperfusion in the rat: effect of blood volume trapped in the kidney, sucrose infusion, and antioxidant treatments. 887 Oct 86

In order to determine whether treatment of animals with an n-3 fatty acid, eicosapentaenoic acid (EPA), could modify renal hemodynamics and physiology after normothermic ischemia, we studied 42 Spraque Dawley rats orally supplemented with either olive oil or a purified lysine salt of EPA for 4 weeks. Four experimental groups were established. Three groups were treated with increasing doses of EPA: 20 mg/kg per day (EPA 20), 40 mg/kg per day (EPA 40) and 80 mg/kg per day (EPA 80), and one group was supplemented with isovolumetric olive oil (OLI). A control group that received neither EPA nor ischemia was also studied. On day 28, right nephrectomy was performed, followed by 30 min of left renal warm ischemia. Basal arterial pressure and renal blood flow (RBF) were monitored in two kidneys before arterial occlusion and continuously thereafter throughout the experiment in one kidney using an electronic transducer and a flowmeter. From 60 to 120 min after the end of ischemia, urine output (microliter/min), glomerular filtration rate (GFR, microliter/min), measured by inulin clearance, and fractional reabsortion of sodium (FRNa) were determined every 20 min. Renal plasma flow (RPF, ml/min) and renal vascular resistance (VR, mm Hg/ml per min) were calculated. RPF was estimated as RBF (1-hematocrit). Before ischemia, the mean RPF and RBF were higher in EPA-fed than in olive oil-fed animals and after ischemia showed a significantly greater increase in EPA-fed animals than in olive oil-fed animals. Mean VR was lower in EPA-fed animals than in olive oil-fed animals, both before arterial occlusion and after ischemia. Mean urine output was similar in the OLI and EPA 20 groups, and significantly higher in the EPA 40 and EPA 80 groups than in the control group. GFR was significantly lower in the OLI and EPA 20 groups than in the control group. Finally, the EPA 40 group showed a similar and the EPA 80 group a slightly higher GFR than the control group. We conclude that EPA supplementation provides protection from renal ischemic-reperfusion injury, and this effect is more evident at higher EPA doses.
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PMID:Changes in renal hemodynamics and physiology after normothermic ischemia in animals supplemented with eicosapentaenoic acid. 895 85

Ischemic renal injury is associated with changes in the expression of a number of genes. Although pH regulation is undoubtedly important during the recovery from ischemia, the expression of acid-base transporters during acute ischemic renal failure has not been studied. In the present study, levels of mRNA encoding the colonic H+-K+-ATPase and four isoforms of the Na+/H+ exchanger (NHE-1, NHE-2, NHE-3 and NHE-4) were measured by quantitative Northern analysis in rat renal cortex and medulla following ischemia-reperfusion injury. Rats were subjected to 30 minutes of renal artery occlusion and then sacrificed either 12 or 24 hours after the occlusion was released. The most striking changes followed 30 minutes of occlusion and 12 hours of reperfusion and involved the mRNA for NHE-3 (involved in HCO3- reabsorption in proximal tubule and thick limb) and colonic H+-K+-ATPase (involved in HCO3- reabsorption in collecting duct). These changes were: (1) a approximately 75% decrease in NHE-3 mRNA in both cortex and medulla; and (2) an approximately 8-fold increase in colonic H+-K+-ATPase mRNA in the cortex. At 12 hours of reperfusion, there was a 66% reduction in the Na+/H+ exchanger (NHE-3) activity as assayed by acid-stimulated 22Na+ influx into brush border membrane vesicles (P < 0.01). After 24 hours of reperfusion, NHE-3 mRNA remained suppressed while cortical colonic H+-K+-ATPase mRNA declined to only twice the control level. Medullary colonic H+-K+-ATPase mRNA did not change significantly. Gastric H+-K+-ATPase mRNA in cortex or medulla remained the same at 0, 12, and 24 hours after reperfusion. Cortical NHE-1 increased mildly at 12 and 24 hours of reperfusion whereas a moderate decrease in NHE-2 and NHE-4 mRNAs was observed in cortex and medulla after both 12 and 24 hours of reperfusion. We suggest that overexpression of colonic H+-K+-ATPase in the early phase of renal reperfusion injury may be responsible for compensatory reabsorption of increased HCO3- load resulting from suppression of NHE-3. This was supported by a fourfold increase in colonic H+-K+-ATPase mRNA in rats treated with acetazolamide, which causes renal HCO3-wasting. Rapid decline in colonic H+-K+-ATPase expression at 24 hours after reperfusion is likely due to reduced HCO3- delivery to distal tubules resulting from decreased GFR. Overexpression of H+-K+-ATPase may be vital to acid-base homeostasis in the early phase of acute ischemic renal failure.
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PMID:Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. 908 76

Chronic graft loss (CGL) may be caused by immunological- or hyperfiltration-mediated tissue destruction. If the hyperfiltration theory is correct, grafts from female donors given to heavy recipients, and having a relatively poor initial function, should suffer an accelerated rate of loss of function. 590 renal transplantations surviving more than 1 yr, including 171 cases of (CGL), were reviewed to identify causes of CGL. No overall influence of recipient or donor sex was found, but female donation resulted in lower acute graft loss and higher CGL. Warm ischemia affected CGL marginally, but cold ischemia < 12 h (excluding living donors) reduced CGL (35 vs. 53% at 10 yr, p < 0.05) and delayed function increased CGL (38% vs. 56% p < 0.001). Patients with a high urea production had high CGL (43% vs. 77%, p < 0.02). No overall effect of recipient weight was found; however 7 patients weighing > 90 kg all had CGL within 10 yr. Creatinine clearance was increasingly correlated to recipient weight (r = 0.23 at 1 yr, 0.38 at 10 yr, p < 0.001). For all years, change in creatinine clearance correlated with change in weight (p < 0.001). The most important factor predicting CGL was creatinine clearance, (> 80 ml/min: 6% at 10 yr; 20-40 ml/min 53%). However, at any level of creatinine clearance, patients with late CGL had a slower loss of renal function. Rate of change of renal function was proportional to creatinine clearance, but only for grafts surviving > 6 yr. Creatinine clearance rose between 3 mths and 2 yr; this rise indicated a good prognosis, was related to recipient weight and weight increase, and was reduced in older donors and cyclosporine treated patients. For patients with low clearance (< 60 ml/min), the increased CGL seen in patients with previous rejection episodes could be explained by their consequent lower clearance, but above this level, rejection episodes had an independent deleterious effect. These findings are compatible with hyperfiltration being the major cause of CGL after 6 yr. Before this immunological factors dominate. Good quality grafts respond to the increased protein load of heavy recipients with an increased GFR. Thus at any time, graft GFR is a function of protein-induced hyperfiltration, immunological graft destruction and hyperfiltration-mediated damage. Hyperfiltration-mediated renal damage is not a problem if the creatinine clearance is greater than 60 ml/min.
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PMID:Hyperfiltration, creatinine clearance and chronic graft loss. 954 17


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