Puromycin aminonucleoside metabolism by glomeruli and glomerular epithelial cells in vitro

Ghiggeri, Gian Marco; Cercignani, Giovanni; Ginevri, Fabrizio; Bertelli, Roberta; Zetta, Lucia; Greco, Fulvia; Candiano, Giovanni; Trivelli, Antonella; Gusmano, Rosanna

doi:10.1038/ki.1991.176

Cited by 30 publications

(16 citation statements)

References 16 publications

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“…syndrome [21]. HSA from PAN rats with massive proteinuria (red curve) and from pair-age normal rats (green curve) are visible as a single yellow curve, which indicates complete overlap of the two proteins (Fig.…”

Section: Electrophoretic Titration Curve Of Hsa In Nephrotic Ratsmentioning

confidence: 96%

“…Nephrosis was induced by a single injection of PAN, 7.5 mg/100 g in normal saline through the tail vein of nonanesthetized animals [21]. Control rats were given normal saline.…”

Section: Experimental Nephrosis In Ratsmentioning

confidence: 99%

“…Bindings to domain I of HSA such as in the case of Ca 21 ions determine, instead, N-A transition that results from a downward pK a shift of histidyl residues [12]. All studies describing transition states of HSA have been performed 'in vitro' but a more detailed analysis in humans is warranted.…”

Section: Introductionmentioning

confidence: 99%

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Transitions of serum albumin in patients with glomerulosclerosis ‘in vivo’ characterization by electrophoretic titration curves

Bruschi¹,

Musante²,

Candiano

et al. 2006

Electrophoresis

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HSA functions as a physiological transporter of solutes and small molecules that induce structural transitions 'in vitro'. Analysis of these transitions requires prior purification of HSA that could introduce bias due to conformational changes. We utilized electrophoretic titration curves to describe a neutral to acid (N-A) transition of HSA directly in sera of seven patients with active focal segmental glomerulosclerosis (FSGS). The divergent electrophoretic profile of HSA was characterized by a shift in the range of pHs between 4.5 and 7.5 with an average variation of free electrophoretic mobility corresponding to loss of 1 positive charge in the pKa protonation range of histidyl residues and should involve domain I of HSA. 'In-gel' determination by maleimide-PEO2-biotin of free SH 34 of domain I showed inaccessibility of the dye at this site in pathological HSA and alkylation with the same complex induced N-A transition in normal HSA. Potential binders of free imidazoles such as Ca++ and/or of SH 34 such as NO were excluded on the basis of direct titration and studies on binding stimulation. This is the first report describing a transition of HSA directly 'in vivo', and the utilization of electrophoretic titration curves was critical to this purpose. This transition appears to be specific to FSGS and is unrelated to the nephrotic syndrome, Ca++ and NO binding. Spectroscopic analysis will elucidate the structural implication.

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Section: Electrophoretic Titration Curve Of Hsa In Nephrotic Ratsmentioning

confidence: 96%

“…Nephrosis was induced by a single injection of PAN, 7.5 mg/100 g in normal saline through the tail vein of nonanesthetized animals [21]. Control rats were given normal saline.…”

Section: Experimental Nephrosis In Ratsmentioning

confidence: 99%

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Transitions of serum albumin in patients with glomerulosclerosis ‘in vivo’ characterization by electrophoretic titration curves

Bruschi¹,

Musante²,

Candiano

et al. 2006

Electrophoresis

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“…Although PAN itself and its metabolites are cytotoxic to GECs [26], it is very unlikely that they are directly responsible for the cytotoxicity of the sera of nephrotic rats, since (a) PAN al 200 gg/ml is not cytotoxic to AECs, while 10% (the concentration added to the medium of AECs) of the calculated concentration in serum of PANinjected rats should be less than 150 pg/ml, (b) PAN is degraded rapidly and PAN and its metabolites are mostly excreted within 24 h [29], whereas the cytotoxic sera were only detectable on days 8-10 and not on day 1 or 4, and (c) most, if not all, of the cytotoxic activity was extracted in the lipid fraction, while metabolites of PAN should be more hydrophilic than PAN, which is water-soluble.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Sera from Rats with Puromycin Aminonucleoside Nephrosis

Natori

Igawa²,

Nakao³

1996

Nephron

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Administration of puromycin aminonucleoside (PAN) to rats induces acute nephrosis with hyperlipidemia, and, in some experimental conditions, it results in chronic focal glomerulosclerosis. In this study, we examined the cytotoxicity of serum from rats with PAN-induced nephrosis, since hypercholesterolemia is considered to cause injury to vascular walls in atherosclerosis, the mechanism of which is analogous to that of glomerulosclerosis. About half of the tested sera from nephrotic rats (9 out of 17) were cytotoxic to cultured aortic endothelial cells. The toxic substance(s) was heat-stable and was extracted in the lipid fraction. Serum levels of triglyceride and cholesterol were markedly higher in the group of rats with cytotoxic serum than in the group with noncytotoxic serum. No cytotoxicity was associated with sera from control rats or the corresponding lipid fractions. Cytotoxic sera were also effective against cultured glomerular epithelial and mesangial cells. These results indicate that cytotoxic lipid is produced in rats with PAN nephrosis and the results raise the possibility that the cytotoxic lipid in nephrotic serum might contribute to lipid-mediated glomerular injury which may induce glomerulosclerosis at a subsequent stage.

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“…Animal models of nephrosis also support a role of oxidants. Minimal renal lesions evolving to glomerulosclerosis are, in fact, produced in rats by infusion of compounds such as puromycin aminonucleoside (PAN) and adriamycin (ADR) that can be classified as oxidants [24,25]. Metabolic studies and protection by anti-oxidants support an entirely oxidative stress in these models.…”

Section: Oxidantsmentioning

confidence: 99%

Regulatory T cells and minimal change nephropathy: in the midst of a complex network

Bertelli

Bonanni

Donato

et al. 2015

Clinical and Experimental Immunology

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SummaryMinimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (T regs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct T reg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating T regs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of T regs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigenpresenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.

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Puromycin aminonucleoside metabolism by glomeruli and glomerular epithelial cells in vitro

Cited by 30 publications

References 16 publications

Transitions of serum albumin in patients with glomerulosclerosis ‘in vivo’ characterization by electrophoretic titration curves

Transitions of serum albumin in patients with glomerulosclerosis ‘in vivo’ characterization by electrophoretic titration curves

Cytotoxicity of Sera from Rats with Puromycin Aminonucleoside Nephrosis

Regulatory T cells and minimal change nephropathy: in the midst of a complex network

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