Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria

Tapia, Edilia; Sánchez-González, Dolores Javier; Medina-Campos, Omar Noel; Soto, Virgilia; Ávila-Casado, Carmen; Martínez-Martínez, Claudia María; Johnson, Richard J.; Rodríguez‐Iturbe, Bernardo; Pedraza‐Chaverrí, José; Franco, Martha; Sánchez‐Lozada, Laura G.

doi:10.1152/ajprenal.90201.2008

Cited by 17 publications

(13 citation statements)

References 52 publications

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“…; Tapia et al. ). Similar to these earlier studies, the anti‐proteinuric effect of PDTC in LPK rats was partial, being evident at week 10 and only reaching statistical significance in the 40 mg/kg twice daily group.…”

Section: Discussionmentioning

confidence: 97%

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Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

Rao

Korgaonkar

et al. 2014

Physiol Rep

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Heterocyclic dithiocarbamates have anti‐inflammatory and anti‐proliferative effects in rodent models of chronic kidney disease. In this study, we tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) reduces the progression of polycystic kidney disease (PKD). Male Lewis polycystic kidney (LPK) rats (an ortholog of Nek8/NPHP9) received intraperitoneal injections of either saline vehicle or PDTC (40 mg/kg once or twice daily) from postnatal weeks 4 until 11. By serial magnetic resonance imaging at weeks 5 and 10, the relative within‐rat increase in total kidney volume and cyst volume were 1.3‐fold (P =0.01) and 1.4‐fold (P < 0.01) greater, respectively, in LPK + Vehicle compared to the LPK + PDTC(40 mg/kg twice daily) group. At week 11 in LPK rats, PDTC attenuated the increase in kidney weight to body weight ratio by 25% (P < 0.01) and proteinuria by 66% (P < 0.05 vs. LPK + Vehicle) but did not improve renal dysfunction. By quantitative whole‐slide image analysis, PDTC did not alter interstitial CD68+ cell accumulation, interstitial fibrosis, or renal cell proliferation in LPK rats at week 11. The phosphorylated form of the nuclear factor (NF)‐κB subunit, p105, was increased in cystic epithelial cells of LPK rats, but was not altered by PDTC. Moreover, PDTC did not significantly alter nuclear expression of the p50 subunit or NF‐κB (p65)‐DNA binding. Kidney enlargement in LPK rats was resistant to chronic treatment with a proteasome inhibitor, bortezomib. In conclusion, PDTC reduced renal cystic enlargement and proteinuria but lacked anti‐inflammatory effects in LPK rats.

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Section: Discussionmentioning

confidence: 97%

“…), and proteinuria (Tapia et al. ), and these effects were correlated with the suppression of NF‐ κ B, metal chelation, and antioxidant activity (Cvek and Dvorak ). However, to our knowledge, the efficacy of PDTC in PKD has not been investigated.…”

Section: Introductionmentioning

confidence: 98%

Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

Rao

Korgaonkar

et al. 2014

Physiol Rep

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“…36 Overload proteinuria reduced activity of several antioxidants enzymes (catalase, GPx, and total SOD) in renal cortex and medulla. 37 Thus it is plausible that changes in antioxidant enzyme activity observed in our study were secondary to differences in proteinuria.…”

Section: Discussionmentioning

confidence: 71%

Proteinuria in aging rats due to low-protein diet during mid-gestation

Joles

Sculley

Langley‐Evans

2009

J Dev Orig Health Dis

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Nephrogenesis in the rat starts mid-gestation and continues into lactation. Maternal low protein (LP) intake leads to renal injury in rats and associates with mild renal injury in humans. We hypothesized that LP during early nephrogenesis or throughout gestation would induce more renal injury in rat offspring than when LP was only present before nephrogenesis. Pregnant rats were fed LP diet (9% casein) at early gestation (LPE, day 0-7), mid (LPM, day 8-14), late (LPL, day 15-22) or throughout gestation (LPA, day 0-22) and compared to controls on 18% casein diet. Offspring were studied at 18 months. Renal injury was assessed by 24 h proteinuria, plasma urea, antioxidant enzyme activities, and apoptosis (Bax/Bcl2). Proteinuria was higher in LPM males and LPE and LPM females. In LPM males glutathione peroxidase activity was lower, while in LPE males catalase activity was higher. Antioxidants were not much affected in females. Bax expression was higher in LPM males and females, while Bcl2 expression was higher in LPA females. Thus even before nephrogenesis (day 0-7), LP impacted on renal integrity in adult life, while LP during a later phase (day 15-22) or throughout gestation had less effect. In summary, for aging rat kidney LP poses the greatest threat when restricted to early nephrogenesis.

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“…Although various studies conducted on animal models of cardiovascular diseases have demonstrated prevention of disease when treatment is initiated early [viz. prior to the onset of complications (21,40,41)], treatment of human diabetes does not normally begin until after the symptoms have become evident and in many instances, when complications are already present. We therefore used aged OLETF rats (a) because long-term diabetic conditions entail severe diabetic complications associated with cardiovascular dysfunction and (b) because no previous study has investigated the therapeutic, not preventive, effect of PDTC on diabetic vasculopathy (in Fig.…”

Section: Discussionmentioning

confidence: 99%

Pyrrolidine Dithiocarbamate Reduces Vascular Prostanoid-Induced Responses in Aged Type 2 Diabetic Rat Model

et al. 2009

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Abstract. It has been shown that enhancement of vasoconstrictor prostanoids plays an important role in the development of cardiovascular diseases. The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC), a low-molecular-weight thiol antioxidant and a potent inhibitor of nuclear factor-κB (NF-κB), on both the response to and production of prostanoids in arterial vessels isolated from rats at the chronic stage of type 2 diabetes. Using aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, control LongEvans Tokushima Otsuka (LETO) rats, and LETO and OLETF rats treated with PDTC (30 mg/ kg, s.c., daily, for 1 week), we measured the production of prostanoids and NF-κB activity. The arachidonic acid-induced contraction and the acetylcholine-induced endotheliumderived contracting factor (EDCF)-mediated contraction in mesenteric arteries were also compared among these groups. OLETF rats exhibited (vs. age-matched LETO rats) the following: increased responses to both arachidonic acid and EDCF and greater productions of PGE 2 and TXA 2 . Treatment with PDTC resulted in the following: 1) reduced arachidonic acid-and EDCFmediated contractions, 2) suppressed the production of prostanoids, and 3) normalized NF-κB activity. These results suggest that PDTC has beneficial effects against the abnormal vasoconstrictor prostanoid signaling present in rats at the chronic stage of type 2 diabetes.

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Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria

Abstract: LG. Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria.

Cited by 17 publications

References 52 publications

Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

Proteinuria in aging rats due to low-protein diet during mid-gestation

Pyrrolidine Dithiocarbamate Reduces Vascular Prostanoid-Induced Responses in Aged Type 2 Diabetic Rat Model

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