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N Perico

Publications and source records attributed to N Perico.

At least 73 records · Page 4Linked to original sources
PubMed1994

Thromboxane A2 receptor blocking abrogates donor-specific unresponsiveness to renal allografts induced by thymic recognition of major histocompatibility allopeptides.

Recent in vitro studies have documented that thromboxane (Tx)A2 induces thymocyte apoptosis by acting on specific receptors abundantly expressed on the surface of immature T lymphocytes. No information is available on the in vivo relevance of this observation in development of self- or acquired tolerance. We and others have previously documented that injection of donor cells into adult thymus of experimental animals induced specific systemic unresponsiveness to allografts in the rat and mouse models. More recently, we have shown that intrathymic injection of synthetic class II major histocompatibility complex (MHC) allopeptides resulted in donor-specific unresponsiveness to renal allografts. The induction of unresponsiveness was abrogated by recipient thymectomy within the first week. We now report the effect of TxA2 blockade on acquired thymic tolerance to renal allografts induced by intrathymic injection of synthetic class II MHC allopeptides in the Wistar-Furth (WF) to Lewis rat strain combination. Administration of the TxA2 receptor blocker prior to transplantation or 2 wk postengraftment completely abrogated the unresponsive state. In addition, inhibiting the TxA2-forming enzyme by aspirin or dexamethasone also abolished the induction of acquired thymic tolerance. Evidence is also provided for a critical "dose" of peptides to be injected into the thymus to induce systemic unresponsiveness to renal allografts. These data, coupled with observations that activated peripheral T cells can circulate through the thymus, provide evidence that TxA2/TxA2 receptor interaction in the thymic microenvironment, leading to anergy/programmed cell death of activated T cells, may play an important role in the development of acquired unresponsiveness in vivo.

Animals↗
PubMed1994

Mechanisms of acquired thymic unresponsiveness to renal allografts. Thymic recognition of immunodominant allo-MHC peptides induces peripheral T cell anergy.

We have recently shown that a single intrathymic injection of synthetic 25mer peptides, representing full sequences of the hypervariable domain of RT1.BuB (4 peptides) and RT1.Du beta (4 peptides) WF class II MHC molecules, 48 hr before transplantation induces donor-specific unresponsiveness to WF rat renal allografts in adult LEW recipients. The induction of unresponsiveness was abrogated by the recipient's thymectomy within the first week after intrathymic injection. Peripheral T cells of long-term survivors exhibited antigen-specific hyporesponsiveness in the LEW x WF MLR. Studies on the mechanisms of induction of acquired thymic unresponsiveness to alloantigen in vivo and in vitro are now reported. First, since we have previously demonstrated in LEW responders that only 4 of the 8 synthetic 25mer peptides, 2 RT1.Du beta and 2 RT1.Bu beta sequences, were immunogenic in vitro and in vivo, we compared the tolerogenicity of the immunogenic versus the nonimmunogenic peptides. While LEW rats intrathymically injected with the nonimmunogenic peptides acutely rejected their renal allografts within 6-10 days, animals injected with the immunogenic peptides did not reject their grafts and are surviving > 100 days with normal allograft function. In vitro studies established that peripheral T cells from intrathymically tolerized animals exhibited antigen-specific hyporesponsiveness in the LEW x WF MLR starting as early as 1 week posttransplant. Immunohistological evaluation of renal allografts from intrathymically tolerized animals 1 week postengraftment showed marked reduction in mononuclear cell infiltrates with no evidence of tubulitis, and marked reduction in intragraft staining for activation and inflammatory cytokines and alloantibodies, as compared with acutely rejecting controls. Systemic administration of 1000 U of rIL-2 daily for 5 days starting on the day of transplantation abrogated the tolerogenic effect of intrathymic MHC allopeptides. Injection of 100 micrograms of a single immunogenic peptide, RT1.Du beta 2 (residues 20-44), into the thymus of responder LEW rats 48 hrs before immunization with RT1.Du beta 2 effected significant reduction of in vitro proliferation of primed lymphocytes to RT1.Du beta 2, an effect that was abrogated by addition of rIL-2 in vitro. In contrast, thymectomy beyond 2 weeks and administration of rIL-2 at 4-6 weeks after transplantation failed to cause rejection. These observations indicate that thymic recognition of immunodominant class II MHC allopeptides leads to peripheral T cell anergy that mediates the induction phase of systemic unresponsiveness to renal allografts. The maintenance phase appears to be mediated by dense anergy or clonal deletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Following an initial decline, glomerular filtration rate stabilizes in heart transplant patients on chronic cyclosporine.

We previously reported that heart transplant patients given cyclosporine for more than 2 years (short-term evaluation) had severe renal lesions and markedly reduced glomerular filtration rate and renal plasma flow (Kidney Int 40:243-250, 1991). We report the analysis of renal function in the same patients after 3 additional years of follow-up (long-term evaluation) while they continued to take cyclosporine. Since the previous evaluation, the dose of cyclosporine was adjusted to maintain stable trough levels and antihypertensive therapy was unchanged. The mean time-averaged dose of cyclosporine during the follow-up was 4.5 +/- 2.1 mg/kg/d. The systolic blood pressure at long-term evaluation (146 +/- 16 mm Hg) was increased (P < 0.05) compared with that at short-term evaluation (140 +/- 13 mm Hg), whereas diastolic blood pressure (long-term 91 +/- 9 mm Hg v short-term 88 +/- 9 mm Hg) and mean blood pressure (long-term 110 +/- 12 mm Hg v short-term 108 +/- 11 mm Hg) did not change significantly. Serum creatinine concentrations at long-term (1.7 +/- 0.3 mg/dL) and at short-term (1.7 +/- 0.4 mg/dL) evaluations were similar. At long-term evaluation the renal plasma flow (300 +/- 64 mL/min/1.73 m2) was not decreased compared with that at short-term evaluation (325 +/- 94 mL/min/1.73 m2), while the glomerular filtration rate increased significantly (43 +/- 15 mL/min/1.73 m2 v 36 +/- 8 mL/min/1.73 m2, respectively; P < 0.05). None of the patients became proteinuric after short-term evaluation; in those patients who were already proteinuric, urinary protein excretion did not increase over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Calcitonin gene-related peptide reduces renal vascular resistance and modulates ET-1-induced vasoconstriction.

Calcitonin gene-related peptide (CGRP) is a novel polypeptide that exerts important effect on the cardiovascular system through its vasorelaxant properties. We studied in vivo in normal rats the effect of acute administration of CGRP on whole kidney function and showed that the intravenous infusion of the peptide resulted in a fall of blood pressure associated with a marked increase in renal plasma flow (RPF) as well as glomerular filtration rate (GFR). These changes were reversible with discontinuation of CGRP infusion. To evaluate whether the renal hemodynamic responses to the peptide were mediated by endogenous vasodilatory prostaglandins of endothelial origin, animals were preexposed to indomethacin, a cyclooxygenase enzyme inhibitor. Inhibition of prostaglandins synthesis with indomethacin failed, however, to prevent the increase in RPF and GFR observed during CGRP infusion. By contrast, NG-nitro-L-arginine methyl ester (L-NAME), which inhibits the synthesis of nitric oxide, a newly discovered endothelium-derived relaxing factor, completely abolished the renal hemodynamic changes induced by CGRP. Moreover, L-arginine infusion in L-NAME-treated rats restored the renal response to CGRP. We have also shown that systemic infusion of CGRP progressively normalized RPF and GFR that were reduced in response to a bolus intravenous injection of the vasoconstrictor endothelin-1. This indicates that CGRP regulates renal hemodynamics and modulates the deleterious effects of vasoconstrictive substances on the kidney.

Animals↗
PubMed1994

Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started.

In rats with streptozotocin-induced diabetes, the effect of an angiotensin-converting enzyme (ACE) inhibitor on the evolution of glomerular injury according to the time at which the treatment is started with respect to the onset of the disease was studied. Three groups of animals were used, a control Group 1 and two groups of diabetic rats treated with insulin (Groups 2 and 3). The latter were monitored until urinary protein excretion reached 40 to 50 mg/24 h (on average, 23 wk after the induction of the diabetes). At this time, Group 2 continued to receive insulin alone, whereas Group 3 was also given the ACE inhibitor moexipril for 8 more wk. Untreated diabetic rats showed a moderate increase in systolic blood pressure that was normalized by moexipril administration. Urinary protein excretion progressively increased during the 8-wk follow-up in untreated diabetics that, at the end of the study, developed moderate glomerular sclerosis. Moexipril treatment lowered urinary protein excretion to a normal range and completely prevented glomerular injury. Three other groups of rats were similarly treated, except that moexipril treatment was started later on (when proteinuria reached 100 to 200 mg/24 h, on average, 32 wk after the induction of diabetes), and were monitored for another 8 wk. Untreated and treated diabetics had comparable blood glucose levels throughout. Systolic blood pressure, significantly increased in untreated diabetic rats, was effectively controlled by moexipril administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Edema of the nephrotic syndrome: the role of the atrial peptide system.

The nephrotic syndrome is associated with an expanded interstitial volume and edema due to sodium and water retention. The mechanisms underlying these abnormalities have been only partially clarified. Renal hypoperfusion has been considered the key event that promotes avid sodium and water reabsorption by the kidney. Hypoperfusion results from hypovolemia, a consequence of urinary protein losses and decreased oncotic pressure. However, in some patients plasma volume is normal or even increased, suggesting that in such cases the cause of sodium and water retention might be independent of systemic events and possibly originates in the kidney. Experimental evidence is now available to support this, but the intrarenal mediator(s) that promote the abnormal salt retention are still not fully clear. Atrial natriuretic peptide (ANP), which increases sodium and water excretion, has been suspected to participate in fluid retention. This is consistent with experimental and human data of a markedly blunted natriuretic and diuretic response to systemic infusion of ANP in the nephrotic syndrome. Recent studies of the mechanisms of the blunted natriuretic and diuretic response to ANP documented an increased activity of renal sympathetic nerves, but the results are controversial. The altered response to ANP also may be related to a defect in the number and affinity of receptor-binding sites for the peptide. Evidence also is available of a possible defect at the level of intracellular cyclic guanosine monophosphate, the second messenger of ANP. The gene encoding for a cyclophilin-like protein, which is increased in sodium-retaining conditions, is upregulated in the kidneys of nephrotic rats, and the infusion of ANP further increases cyclophilin-like protein mRNA. Thus, multiple factors probably act in concert to induce edema formation in the nephrotic syndrome. In this review we specifically address the tubular insensitivity to the natriuretic and diuretic action of ANP, which could be an important initiating event and could possibly contribute to sustaining the edema.

Animals↗
PubMed1993

Calcium channel blockers protect transplant patients from cyclosporine-induced daily renal hypoperfusion.

Renal toxicity, possibly due to vasoconstriction and vascular injury, is the most relevant side-effect of chronic cyclosporine (CsA) therapy given to prevent graft rejection. In kidney transplant recipients each oral dose of CsA is invariably followed by a transient reduction in renal plasma flow (RPF) and glomerular filtration rate (GFR) that results from a form of acute reversible hypoperfusion. We sought to determine whether the Ca2+ channel blocker, lacidipine, prevented CsA-associated renal hypoperfusion in these patients. Parallel studies on CsA pharmacokinetics, renal function parameters (GFR and RPF), as inulin and p-aminohippurate (PAH) clearances, respectively, and urinary excretion of the vasoconstrictor endothelin in 10 consecutive renal transplant patients given CsA as a part of their immunosuppressive therapy were performed. Patients were studied at different time intervals after CsA alone, CsA and lacidipine (4 mg/day), and again seven days after lacidipine withdrawal. In all patients basal RPF and GFR declined on average 51% (139.3 +/- 20.7 ml/min/1.73 m2) and 50% (32.5 +/- 5.8 ml/min/1.73 m2), respectively, two to four hours after maximum blood CsA concentration was reached. As blood levels of CsA returned to trough, both parameters progressively increased to baseline. Lacidipine administration completely prevented the fall in RPF (pre-CsA: 277.1 +/- 23.6; 6 hr post-CsA: 304.5 +/- 31.1 ml/min/1.73 m2) and GFR (pre-CsA: 66.6 +/- 8.1; 6 hr post-CsA: 70.1 +/- 9.8 ml/min/1.73 m2). When lacidipine treatment was discontinued the abnormal RPF and GFR response to CsA administration was again observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression.

We previously demonstrated that urinary endothelin excretion is increased in rats with extensive renal mass reduction, a model of progressive renal disease. Here we explored whether the increased urinary endothelin in this model were due to induction of renal pre-pro-endothelin-1 gene and whether changes in endothelin synthetic pathway correlated with the development of glomerulosclerosis. Four groups of rats with renal mass reduction and four groups of sham-operated control rats were studied 7, 30, 60 and 120 days after the surgical procedure. Urinary protein excretion in renal mass ablation animals did not differ from controls at seven days, but was already significantly elevated (P < 0.01) 30 days after surgery. Then proteinuria progressively increased in rats with remnant kidney at values above 400 mg/day at day 120. Serum creatinine concentration also progressively increased with time in renal mass ablation rats, unlike sham-operated animals, and values were significantly different (P < 0.01) at each of the points considered. Rats with renal mass reduction, unlike sham-operated animals, developed focal glomerulosclerosis that affected 8% of glomeruli at day 30, and 24% of glomeruli at day 120. Seven days after renal mass reduction renal pre-pro-endothelin-1 (pre-pro ET) mRNA was comparable to that of sham-operated rats, while a 2.5-, 5- and fourfold increase in 2.3 Kb pre-proET-1 transcript was observed at 30, 60 and 120 days, respectively. Urinary excretion of endothelin was significantly elevated (P < 0.01) in rats with renal mass reduction with respect to sham-operated rats, starting from 30 days after surgery and increased further thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Thymic recognition of class II major histocompatibility complex allopeptides induces donor-specific unresponsiveness to renal allografts.

Recent data show that intrathymic injection of allogeneic cells induces donor-specific unresponsiveness to allografts. There is also evidence to suggest that, in addition to recognizing intact MHC molecules, T cells can recognize processed MHC peptides, although the role of this indirect mode of allo-recognition in allograft rejection is unknown. We report that a single intrathymic injection of 100 micrograms of a mixture of eight 25-mer synthetic polymorphic class II MHC allopeptides, representing the full-length sequence of RT1.Bu beta and RT1.Du beta (WF) into incompatible (RT1l) LEW recipients, induced a state of long-term unresponsiveness to subsequent engraftment 2 days later of WF, but not third party (RT1n) BN renal allografts. Intrathymic injection of 100 micrograms of either RT1.Bu beta or RT1.Du beta peptide mixtures alone were insufficient to prolong renal allograft survival. Intravenous or intrasplenic injection of the allopeptide mixture did not affect renal allograft survival, establishing the role of thymic recognition of class II MHC allopeptides in inducing systemic unresponsiveness. The induction of intrathymic donor-specific unresponsiveness was abrogated if thymectomy was performed on the day of renal transplantation or 5 days later. PBLs from long-term surviving animals exhibited marked reduction of proliferation to WF, but not third party BN stimulator lymphocytes in the standard mixed lymphocyte response assay in vitro. These observations emphasize the role of recognition of processed MHC molecules in vascularized allograft rejection and confirm the role of the thymus in acquired systemic tolerance to alloantigens.

Animals↗
PubMed1993

Renal handling of sodium in the nephrotic syndrome.

In the nephrotic syndrome abnormal sodium and water retention occurs at the kidney level that ultimately causes expansion of interstitial volume and edema. The mechanisms and factors involved remain ill defined. The traditional view has considered hypovolemia, due to urinary protein losses and decreased oncotic pressure, as the afferent stimulus of a complex pathway of responses that come together to enhance reabsorption of sodium and water along the nephron. However, given the fact that only a minority of nephrotic patients have low plasma volume, it has been hypothesized that sodium retention by the kidney is a primary phenomenon occurring in response to intrarenal rather than systemic mechanisms. Experimental evidence is available to support this possibility, and indicates that distal nephron sites are involved in avid sodium retention in the nephrotic syndrome. Several studies have been designed to establish the role of neurohumoral mediators, including the renin-angiotensin-aldosterone axis and sympathetic nervous system. These data suggest that although activation of these systems may contribute to salt retention, they may be minor factors in this process. Recently, attention has focused on atrial natriuretic peptides (ANP), which increase sodium and water excretion in experimental animals and humans. A markedly blunted natriuretic and diuretic response to the systemic infusion of ANP has been reported in the nephrotic syndrome. A defect in the number and affinity of receptor binding sites for the peptide as well as in the level of intracellular cyclic guanosine monophosphate, the second messenger of ANP, has recently been investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗
PubMed1993

Renal cyclophilin-like protein gene expression parallels changes in sodium excretion in experimental nephrosis and is positively modulated by atrial natriuretic peptide.

Experimental evidence is available to indicate that intrarenal mechanisms play a role in the impaired salt excretion of nephrotic syndrome by multiple and still incompletely defined mediators. It is documented herein that the gene encoding for cyclophilin-like protein (Cy-LP) is up-regulated in renal medulla from adriamycin (ADR)-treated rats as compared with control animals. In the cortex of rats with ADR nephrosis, no change in Cy-LP as compared with that in controls was found for the entire observation period. By contrast, in the medulla of nephrotic rats, Cy-LP gene expression was significantly higher than in controls. Values of urinary Na excretion were inversely correlated to Cy-LP mRNA expression levels. Because in ADR nephrosis a blunted natriuretic response to ANP has been previously reported, it was investigated whether ANP infusion modulated Cy-LP mRNA in the renal medulla. ADR-treated rats, but not control rats, infused for 1 h with ANP (1 microgram/kg.min) had a significant (P < 0.05) increase in medullary Cy-LP mRNA as compared with nephrotic animals receiving the vehicle alone. These findings might be taken to suggest that renal Cy-LP gene expression is positively modulated in nephrotic syndrome and parallels changes in sodium excretion.

Animals↗
PubMed1993

Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

Angiotensin Receptor Antagonists↗
PubMed1993

Colchicine allows prolonged survival of highly reactive renal allograft in the rat.

Colchicine, with its immunosuppressive properties, has been used with beneficial effects in autoimmune diseases. Whether colchicine, by virtue of the above properties, could attenuate the process of kidney allograft rejection in the rat is investigated in this report. Untreated Lewis rats (N = 6) given an incompatible kidney allograft from Brown-Norway rats rejected the graft within 12 days. Colchicine at a daily ip dose of 40 (N = 6) or 10 (N = 4) micrograms/kg promoted long-term survival (> 170 days) of major histocompatibility complex-incompatible kidney grafts. Animals (N = 4) given 4 micrograms of colchicine per kilogram had a graft failure within 10 days. Experiments have also been performed to evaluate the effect of colchicine withdrawal at different time intervals from transplantation on subsequent allograft survival. Colchicine (40 micrograms/kg per day ip) was given for 12, 6, or 1 mo or for 15 days to an additional four groups of six animals each without any other immunosuppressants. The withdrawal of colchicine did confer long-term inhibition of the immune system in animals treated for at least 1 mo, as documented by a graft survival of more than 80 days. By contrast, those animals who discontinued colchicine after only 15 days of treatment had graft rejection within the next 8 days. Mixed lymphocyte culture experiments showed a significant (P < 0.01) reduction of the proliferation of peripheral blood lymphocytes taken from all groups of animals 30 days after colchicine withdrawal when challenged with Brown-Norway lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗