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A Fogo

Publications and source records attributed to A Fogo.

At least 73 records · Page 4Linked to original sources
PubMed1995

Strategic locus for the activation of the superoxide dismutase gene in the nephron.

Upon exposure to a transient ischemia, the distal tubule of the kidney often escapes the severe damage which afflicts the proximal tubule. To ascertain whether this feature of the distal tubule is attributable to its intrinsic cellular properties, we focused on two pairs of unique tubule segments; distal versus proximal convoluted tubules in the superficial cortex and distal versus proximal straight tubules in the outer stripe of the outer medulla. These tubules were chosen because, firstly, they can be identified by morphology and immunostaining, and secondly, each pair has the same anatomical relationship to the circulation. Detailed morphometric analyses were performed six hours following unilateral transient ischemia in adult rats to semiquantitate the local tissue damage in these specific nephron segments. The architecture of the distal convoluted and straight tubules was remarkably well preserved, contrasting to the moderate to extensive necrotic changes seen in the proximal tubules. In search of the potential intrinsic cellular mechanism that underlies the observed difference, we examined the segmental distribution along the nephron of manganese superoxide dismutase gene transcripts by in situ hybridization. This antioxidant enzyme gene was expressed primarily in the distal tubules with contrastingly low levels of expression in the proximal tubules. Moreover, following ischemia-reperfusion, this distal tubule-dominant pattern was further accentuated immediately following reperfusion. The study indicates that the marked difference between the proximal and distal tubules in their susceptibility to injury in vivo is attributable to their intrinsic cellular properties, which include the local level of antioxidants.

Animals↗
PubMed1995

Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation.

Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg-1-). Postnatally, Atg-1- animals show a modest delay in glomerular maturation. Although Atg-1- animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-beta1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla.

Aging↗
PubMed1995

Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity.

Chronic treatment with cyclosporine (CsA) is limited not only by glomerular hypofiltration but also by structural damage. The pathogenesis of these nephrotoxicities was studied in a model of chronic CsA-induced renal damage. Salt-depleted rats were treated with daily CsA (15 mg/kg sc) for approximately 3 weeks, at which time renal function was measured and kidneys were harvested for morphologic assessment. A separate group of rats (CsA + BQ123) were identically treated with CsA but in addition also received simultaneous treatment with a specific endothelin A (EtA) receptor antagonist, BQ123, which was continuously delivered via sc osmotic pump (1 mg/kg per hour) and maintained throughout the study. Chronic CsA treatment caused profound functional and structural damage, although blood pressure was normal (102 +/- 6 mm Hg); GFR was 0.05 +/- 0.02 mL/min per 100 g body wt, and RPF was 0.15 +/- 0.06/100 g body wt. Renal injury was scored on a scale of 0 to 4 and showed dilation/vacuolization of 1.07 +/- 0.29 and tubulointerstitial fibrosis of 0.78 +/- 0.17. Arteriolopathy was present in 78 +/- 4% of arterioles. Chronic antagonism of the EtA receptor preserved renal function: GFR was 0.15 +/- 0.03 mL/min per 100 g body wt, and RPF was 0.32 +/- 0.08/100 g body wt (P < 0.05 for GFR versus CsA). Blood pressure was not affected: 104 +/- 8 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The effect of selective growth hormone defect in the progression of glomerulosclerosis.

The role of endogenous growth hormone (GH) in the progression of glomerulosclerosis was examined in a new mutant strain of Sprague-Dawley (SD) rats with a selective GH gene defect. Fifteen spontaneous dwarf [GH(-)] rats and 10 SD rats underwent subtotal nephrectomy (Nx) or sham operation. Twelve weeks after Nx, the mean arterial pressure, glomerular filtration rate, urinary protein excretion rate, glomerular size, and frequency of glomerulosclerosis were examined. Marked elevation in mean arterial pressure was seen in both SD/Nx and GH(-)/Nx rats. In both strains, the glomerular filtration rate at 12 weeks after Nx was approximately 50% to 60% of that seen in the respective Sham-operated rat groups. The urinary protein excretion rate increased significantly only in the SD/Nx rats. The glomerular size, expressed as the ratio of glomerular volume to body weight, increased by 200% in the SD/Nx rats compared with the SD/Sham rats, in marked contrast to the 70% increase in the GH(-)/Nx rats compared with the GH(-) rats. The frequency of glomerulosclerosis in the GH(-)/Nx rats (1.0 +/- 0.5%) was significantly lower than that in the SD/Nx rats (16.7 +/- 2.8%). The frequency of glomerulosclerosis correlated with glomerular hypertrophy in both the SD and GH(-) rats (r = 0.88 and 0.67, respectively). These results show that the progression of glomerular sclerosis was markedly attenuated in the GH-defective rats. This attenuation of structural injury was correlated with a marked decrease in glomerular hypertrophy. These studies indicate that this specific growth regulatory peptide of endogenous origin plays an important determining role in the progression of glomerulosclerosis.

Analysis of Variance↗
PubMed1994

Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechanisms.

Rats with puromycin aminonucleoside (PAN) nephrosis were given either angiotensin I converting enzyme inhibitor (ACEI), angiotensin II type 1 receptor antagonist (Ang IIRA), or no treatment for four weeks and were then monitored for an additional 12 weeks. In untreated PAN rats, proteinuria reached a maximum at two weeks (271 +/- 38 mg/day). Proteinuria in this early phase was markedly attenuated by ACEI (96 +/- 35 mg/day, P < 0.01), but unaffected by Ang IIRA (306 +/- 34 mg/day). Acute administration of a bradykinin antagonist substantially dampened the antiproteinuric effect of ACEI in PAN rats, resulting in an average increase in proteinuria of 41 +/- 14% in ACEI-treated rats (P < 0.05, ACEI vs. ACEI+bradykinin antagonist). Acute phase therapy for four weeks with ACEI or Ang IIRA did not attenuate subsequent glomerulosclerosis. Separate groups of PAN rats with similar degree of glomerulosclerosis, assessed at 16 weeks after PAN by renal biopsy, were then treated as follows: ACEI [50 mg/liter drinking water (DW), or 200 mg/liter DW], Ang IIRA (20 mg/liter DW, or 80 mg/liter DW) or no treatment, starting after renal biopsy. Whereas glomerulosclerosis increased from biopsy to autopsy at 28 weeks with emergence of low grade proteinuria in untreated PAN rats, proteinuria was absent and glomerulosclerosis was ameliorated or reversed in ACEI and Ang IIRA groups. The results indicate that the early phase proteinuria of PAN nephropathy is independent of Ang II, and that the antiproteinuric effect of ACEI is, at least in part, channeled through activation of bradykinin, whereas the subsequent progression of glomerulosclerosis is caused by a mechanism involving endogenous Ang II actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1994

Consequences of acute nitric oxide synthesis inhibition in experimental glomerulonephritis.

To assess the functional relevance of the enhanced glomerular nitric oxide (NO) synthesis during acute nephrotoxic serum (NTS) nephritis, a NO synthesis inhibitor (NOI) NG-monomethyl-L-arginine was administered to normal (N + NOI) and acutely nephritic (NTS + NOI) Munich-Wistar rats, and systemic and glomerular hemodynamic responses were contrasted with those observed in vehicle-treated normal and nephritic (NTS) controls. Urinary protein excretion rates were equal in normal and N + NOI rats but were markedly elevated in NTS animals and further increased in NTS+NOI. NO inhibition in normal animals (normal versus N + NOI) led to reductions in glomerular plasma flow rate and the glomerular capillary ultrafiltration coefficient (Kf) and elevations in afferent and efferent arteriolar resistances and net transcapillary hydraulic pressure difference (delta P), as well as an increase in systemic arterial pressure. The increase in delta P offset the falls in glomerular plasma flow rate and Kf, and GFR was preserved. Directionally similar responses in efferent resistance occurred in NTS + NOI compared with NTS, however, afferent resistance was not further affected by NOI. Additionally, although Kf was severely depressed in the NTS group (approximately 60% versus normal), it was not further depressed by NOI treatment. Polymorphonuclear cell (PMN) infiltration/glomerulus was mildly increased in N + NOI over normal. In contrast, PMN number in NTS + NOI rats was diminished as compared with NTS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The molecular basis of increased glomerulosclerosis after blockade of the renin angiotensin system in growth hormone transgenic mice.

BACKGROUND: Angiotensin converting enzyme inhibitor (ACEi) therapy delays the onset of renal failure in diabetic nephropathy and inhibits or delays the onset of proteinuria in several animal models. MATERIALS AND METHODS: We examined this question using a transgenic model of chronic glomerulosclerosis caused by an excess production of growth hormone (GH) in which there is progressive glomerular scarring leading to uremia. In addition, since GH mice do not have systemic hypertension or an elevated glomerular filtration rate, we could address the question of whether ACEi or angiotensin II receptor antagonists (AII RA) had an effect on the development of glomerulosclerosis under these conditions. Since excess matrix accumulates in glomerulosclerosis because of alterations in the balance between its synthesis and degradation, we examined the effect of ACEi and AII RA on these parameters. RESULTS: Systemic blood pressure was unaffected by ACEi treatment, but the glomerular filtration rate decreased 85%. ACEi-treated mice had increased mesangial deposition of type I collagen and decreased 105 kD complex collagenase activity. In addition, ACEi-treated GH mice had increased glomerular alpha 1 type I collagen, alpha 1 type IV collagen, and alpha-smooth muscle cell actin mRNAs. No changes were noted in beta actin, or 72 kD metalloproteinase mRNAs. The result of these changes was a net increase in sclerosis. Surprisingly, GH mice treated with ACEi or AngII RA developed marked renal arteriolar lesions. CONCLUSIONS: In some forms of glomerulosclerosis, the lesions develop independently of angiotensin II. Pharmacological inhibition of angiotensin II, in this circumstance, may aggravate the lesions through disregulation of the levels and the balance between glomerular matrix synthesis and degradation.

Actins↗
PubMed1993

Endothelin: potential role in development and disease.

Endothelin is a vasoconstrictor substance, initially isolated from porcine endothelial cell supernatant, which has a structure different from any other mammalian peptide. An extensive array of biological activities has been ascribed to endothelin which, besides having unrivaled vasoconstrictive effects, modulates neurotransmission, regulates other hormones and neurotransmitters, and also has potent hyperplastic/hypertrophic effects. These observations have suggested important roles for endothelin in pathophysiological conditions and also in normal development. Inhibition of endothelin activity can decrease vasoconstriction associated with pathophysiological settings. Inhibition of endothelin activity also decreases mitogenesis and therefore cellular proliferation and growth, thereby supporting a role for endothelin in processes which are an integral part of normal development.

Animals↗
PubMed1993

Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy.

Renal diseases characterized by Congo red-negative extracellular fibrillary deposits, either organized arrays of larger, microtubular fibrils (immunotactoid glomerulopathy [IT]) or smaller, randomly organized fibrils (fibrillary glomerulonephritis), have been recognized recently. The clinical significance, if any, of the distinction of these patterns has not been determined. On review of all renal biopsy specimens evaluated in a private referral renal pathology laboratory over the last 11 years, 26 cases with fibrillary glomerulonephritis pattern were identified and compared with our six most recent cases with the IT pattern. The fibrillary glomerulonephritis patients, 17 women and nine men, had an average age of 50 +/- 2 years and contributed 1% of the renal biopsy specimens examined. All patients had marked proteinuria and 16 had microscopic hematuria. Follow-up at 23 +/- 5 months in 25 of these patients revealed end-stage renal disease in 11 patients (44%) and one death due to renal failure. End-stage renal disease developed an average of 10 +/- 5 months after biopsy. One patient developed multiple myeloma. Twenty-four renal biopsy specimens showed proliferation, with crescents in seven. Immunofluorescence showed moderate to intense staining for immunoglobulin G and weaker staining for C3, in a predominantly mesangial pattern, with weaker glomerular basement membrane (GBM) staining, corresponding to electron microscopic deposit localization. In four cases, linear GBM staining by immunofluorescence corresponded to extensive subendothelial or transmembranous deposits. The average fibril diameter was 14.0 +/- 0.5 nm (range, 10.4 to 18.4 nm). Immunotactoid glomerulopathy patients (three women and three men) were significantly older, 62 +/- 2 years (P < 0.025). All had marked proteinuria, with microscopic hematuria in two patients. Associated hematopoietic diseases were present in four patients, with monoclonal proteins and/or abnormal plasma cell proliferation in three. One patient died of nonrenal causes. The remaining five patients have stable renal function at 20 +/- 5 months. Biopsy specimens showed proliferative (n = 3) or membranous-like (n = 3) patterns. Immunofluorescence showed immunoglobulin G and weaker C3 staining in a granular GBM pattern, with lesser mesangial staining. The microtubular fibril diameter was on average 43.2 +/- 10.3 nm (range, 16.8 to 90.0 nm). Thus, fibrillary glomerulonephritis and IT can be separated based on ultrastructurally distinct features. Patients with fibrillary glomerulonephritis are less likely than those with IT to have associated hematopoietic disease and also have poorer renal survival. We propose that classification based on these morphologic differences appears to have clinical significance.

Adult↗
PubMed1993

Intrarenal localization of angiotensin II type 1 receptor mRNA in the rat.

We examined intrarenal localization of angiotensin II type 1 receptor (AT1) mRNA in kidneys of normal adult male Munich Wistar rats using the methods of reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. For RT-PCR, we used a rat AT1 subtype A (AT1A)-specific oligonucleotide primer pair. To semi-quantitatively assess the expression level of AT1 mRNA among several regions of kidney, AT1 cDNA was coamplified with beta-actin cDNA. When compared to the level in the adrenal gland (expressed as 100%), the level of AT1 mRNA was markedly higher in glomeruli (273 +/- 69%), followed in intensity by the renal papilla (151 +/- 57%), renal cortex (139 +/- 19%), and renal medulla (114 +/- 35%). In situ hybridization studies, using a 479 bp nucleotide fragment from AT1A-coding exon as a probe, also revealed a glomerular preponderant pattern of AT1 mRNA localization. Thus, within the glomerulus, AT1 mRNA localized in mesangial areas, predominantly at the vascular pole. In the vascular components of the juxtaglomerular apparatus (JGA), namely the terminal portion of the afferent arteriole (that is, immunohistochemically renin-positive site) and extraglomerular mesangial cells, the latter showed AT1 mRNA localization in the non-manipulated kidney, while AT1 mRNA was undetectable in the arteriole outside the JGA. The kidneys of rats treated with an angiotensin I converting enzyme inhibitor (ACEI) showed extension of the AT1 mRNA localization on the afferent arteriole toward the interlobular artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition.

We studied the effects of interruption of the renin-angiotensin system (RAS) in rats that were volume depleted by water deprivation for 48 hours (AWD) with/without furosemide (AWD + F), a condition known to activate RAS. Following baseline micropuncture, AWD rats (N = 6) were treated with a specific angiotensin II type 1 receptor antagonist (AIIRA; 4 mg/kg body wt bolus i.v. and then continuous infusion) and glomerular hemodynamics compared to those obtained during angiotensin I converting enzyme inhibitor treatment (ACEI; 24 mg/kg bolus i.v. and then continuous infusion). Systemic blood pressure decreased equally following AIIRA and ACEI. Single nephron glomerular filtration rate (SNGFR) increased from baseline following AIIRA (24 nl/min vs. 30, P < 0.025). While a decrease in efferent arteriolar resistance (RE) reduced glomerular capillary pressure (PGC; 67 mm Hg vs. 60, P < 0.05), this change in RE together with decrease in afferent arteriolar resistance (RA), enhanced glomerular plasma flow rate (QA; 80 nl/min vs. 111). Antagonizing angiotensin II receptor increased QA which, together with the tendency to increase glomerular capillary ultrafiltration coefficient, Kf, served to improve glomerular filtration. By contrast, although inhibition of the angiotensin I converting enzyme caused greater vasodilatation, no increase in SNGFR occurred. The lack of response in filtration after ACEI was due to a further fall in PGC to 52 mm Hg (P < 0.01 vs. AIIRA), reflecting profound reduction in RE. Since ACEI but not AIIRA potentiates bradykinin activity we examined effects of a specific bradykinin antagonist (Hoe).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1993

The effects of surgery and acute rejection on glomerular hemodynamics in the transplanted rat kidney.

The effects of surgery and acute rejection on glomerular hemodynamics in the transplanted rat kidney are examined. Kidneys were transplanted from Munich-Wistar (MW) rats to syngeneic controls and MHC-incompatible PVG strain recipients. We report on 4 groups of animals: (1) two-kidney control MW rats; (2) unilaterally nephrectomized MW rats (UNX); (3) renal transplantation from MHC-identical MW littermates and removal of native kidneys (SYN); and (4) transplantation from MW donors to MHC-incompatible PVG rats and removal of native kidneys (ALLO). Glomerular filtration rate (GFR), single-nephron (SN)GFR, and glomerular capillary pressure (PGC) in SYN kidneys were depressed as compared to those in UNX (GFR, 1.41 +/- 0.08 vs. 0.80 +/- 0.08 ml/min; SNGFR, 67.2 +/- 4.8 vs. 44.7 +/- 6.6 nl/min; and PGC, 67 +/- 2 vs. 48 +/- 4 mmHg, UNX vs. SYN, respectively, P < 0.05). GFR and SNGFR in ALLO kidneys, however, were depressed even further (GFR, 0.40 +/- 0.05 ml/min; SNGFR, 13.8 +/- 1.8 nl/min; P < 0.05 for UNX vs. ALLO and SYN vs. ALLO). Afferent arteriolar resistance (RA) was increased greater than 4-fold (UNX, 1.01 +/- 0.15 10(10) dyn.sec.cm-5; SYN, 1.37 +/- 0.36 10(10) dyn.sec.cm-5; ALLO, 4.76 +/- 0.74 10(10) dyn.sec.cm-5 [P < 0.05, UNX vs. ALLO and SYN vs. ALLO]). This led to a precipitous fall in initial capillary flow rate in ALLO rats. These studies reveal the presence of moderate reductions in SNGFR and PGC in the nonrejecting transplanted kidney, which may relate to as yet unidentified consequences of the transplant surgery. More significantly, the principal mechanism leading to the reduced GFR characteristic of acute allograft rejection is identified as severe preglomerular vasoconstriction.

Acute Disease↗
PubMed1992

Severe arteriosclerosis in the kidney of a cocaine addict.

Cocaine abuse has been associated with sudden cardiac death with coronary artery thrombosis with or without underlying vessel disease. Additional vascular beds thus far implicated in cocaine-associated arteriopathy include thoracic and abdominal aorta, and pulmonary, cerebral, and placental vessels; abnormalities include vasospasm, thrombosis, and accelerated atherosclerosis. We report the case of an adult male cocaine user with severe arteriosclerosis of renal vessels, and suggest that cocaine may also affect the renal vasculature.

Adult↗
PubMed1992

Reduced activity of antioxidant enzymes underlies contrast media-induced renal injury in volume depletion.

Oxidant-mediated renal injury has been suggested as an important mechanism of acute renal failure induced by contrast media. Since volume depletion has been recognized as a predisposing factor for contrast media nephropathy, the present study was designed to characterize host-defense mechanisms against oxidant-mediated renal injury during volume depletion. Antioxidant enzyme activities in renal cortex were compared between acutely water deprived (WD, 72 hours) and non-WD rats. WD rats had reduced activities of catalase and superoxide dismutase activities (on average, 48% and 60% of values in non-WD, respectively). In separate groups of WD rats, saline or one of three different contrast media, namely diatrizoate meglumine/diatrizoate sodium (DTZ), ioxaglate meglumine/ioxaglate sodium (IXG), and iohexol (IHX) was injected. Both GFR and renal plasma flow rate, measured 24 hours later, was some 50% less in DTZ-injected than saline-injected WD rats. WD rats treated with IXG and IHX had similar GFR to saline-treated rats. In DTZ-treated WD rats, specific products of membrane lipid peroxidation, phosphatidylcholine and phosphatidylethanolamine hydroperoxide, determined by chemiluminescent HPLC, were more than two-fold higher than saline, IXG, or IHX-treated WD rats. DTZ did not induce renal dysfunction and enhance lipid peroxidation in non-WD rats. Therefore, DTZ appeared to induce oxidant-mediated injury only in WD rats. When WD rats were pretreated with polyethylene glycol-coupled catalase (1.4 mg x 2 days), renal cortical catalase activity remained at a level similar to that of non-WD rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure.

Previous studies in experimental models of progressive renal failure have shown that the capacity of antihypertensive drugs to protect glomeruli from sclerosis is often unpredictable from their effect on systemic blood pressure. The present study was undertaken to ascertain whether this systemic blood pressure-independent structure-preserving effect of antihypertensives, particularly angiotensin II converting enzyme inhibitors (ACEI), is confined to the glomerulus or not, as well as whether this effect is mediated via angiotensin II (Ang II). The following experimental drug regimens were used in the rat model of subtotal nephrectomy (sNPX): so-called triple therapy [TRX; a combination of reserpine 5 mg/liter drinking water (DW), hydralazine 80 mg/liter DW and hydrochlorothiazide 25 mg/liter DW], or ACEI (either captopril, CPL, 600 mg/liter DW, enalapril, ENL, 400 mg/liter DW or lisinopril, LSL, 200 mg/liter DW), or a novel Ang II receptor antagonist (Ang IIR, L-158,809, 20 mg/liter DW). These dosages were identified in pilot studies to be the minimum required to control systemic blood pressure in the early phase up to 12 weeks. In addition, a separate group was treated with a higher dose of L-158,809 (80 mg/liter DW) with equipotent systemic pressor effect. Treatment was initiated eight weeks after subtotal nephrectomy following renal biopsy, and animals were sacrificed at 16 weeks. In ACEI treated rats, carotid arterial wall thickening (WT), defined as ratio of media thickening to radius of outer vessel wall, was similar to normal age-matched control (0.073 in all ACEI treated rats, vs. 0.074 in normal control) and significantly less than with TRX (ratio 0.118) or untreated sNPX (0.130). Even more remarkably, coronary arteriole WT in ACEI-treated rats averaged 0.139, a value less than one half and one third of TRX (0.298) and untreated sNPX control (0.388), respectively. Similar results were obtained for mesenteric artery WT. These findings were closely paralleled by changes of glomerular sclerosis. In untreated sNPX control rats, glomerular sclerosis increased from biopsy to autopsy specimens by an average of 458%. Although TRX dampened the degree of increase in sclerosis to on average 212%, this protective effect was far less than that achieved by ACEI. In the latter, sclerosis increased on average only 65% from biopsy to autopsy. Although all ACEIs were more effective than TRX, captopril and lisinopril groups showed greatest benefit at these doses. Ang IIR also protected renal and extrarenal structures with 34% increase of sclerosis index in low dose and WT 0.088, 0.117 and 0.112, respectively in carotid, mesenteric and coronary arteries.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1992

Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

Effects of prolonged growth hormone administration in rats with chronic renal insufficiency.

Recombinant hGH (rhGH) augments short-term linear growth in experimental animals and children with chronic renal failure. Significant augmentation of final height, however, requires prolonged growth hormone therapy during years of growth. The effects of prolonged rhGH treatment on linear growth, progression of renal dysfunction, and longevity in the setting of renal insufficiency are unknown. We examined at 9, 15, and 25 wk growth in length and weight, glomerular filtration rate measured by inulin and creatinine clearance, food efficiency (g ingested/weight gained), and survival in treated (U-GH) and untreated (U) 75% nephrectomized uremic rats and in treated (S-GH) and untreated (S) sham-operated rats. We also measured kidney weight to body weight ratios at the time the rats were killed. Treatment was rhGH 1.0 mg s.c. three times a week during wks 4-12 of life. Length of U-GH rats was greater than that of U rats (p less than 0.05) at 15 and 25 wk (but not at 9 wk) and equal to that of S rats throughout the study. Length of S-GH rats exceeded that of S rats. At 9 wk, weight was diminished in both U and U-GH rats (p less than 0.05) versus S and S-GH rats; by 15 wk, U-GH rat weight was equal to S rat weight. Glomerular filtration rate measured by creatinine was markedly reduced in U and U-GH rats and did not increase in response to prolonged rhGH in either U-GH or S-GH rats. Diminished food efficiency of U rats versus S rats (p less than 0.05) was not improved significantly by rhGH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗