Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats.

Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent K+ channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/day. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that mitochondrial Ca2+ uniporter levels in glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through mitochondrial Ca2+ uniporter modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.NEW & NOTEWORTHY Our findings suggest that the mitochondrial Ca2+ uniporter may be an upstream regulator of manganese superoxide dismutase and indicate a biochemical basis for the interaction between the ATP-sensitive K+ channel and Ca2+ signaling. We believe that our study makes a significant contribution to the literature because our results indicate that the ATP-sensitive K+ channel may be a potential therapeutic target for podocyte injury and nephrotic syndrome.

Shensu IV prevents glomerular podocyte injury in nephrotic rats via promoting lncRNA H19/DIRAS3-mediated autophagy.

Shensu IV is a Chinese prescription well-known for its function in treating chronic kidney diseases. However, the potential mechanisms underlying how Shensu IV exerts its effects remain unclear. In the present study, we investigated the effects of Shensu IV on glomerular podocyte injury in nephrotic rats and puromycin-induced injury in cultured podocytes, and assessed the associated molecular mechanisms. Liquid chromatography-mass spectrometry (LC-MS) results showed that the main components of Shensu IV were l-Carnitine, P-lysoPC (LPC) 16:0, Coumaroyl tyramine, Tetramethylpyrazine, LPC 18:1, Choline, (S,S)-Butane-2,3-diol, and Scopoletin. We further found that nephrotic rats displayed pathological alterations in kidney tissues and ultrastructural changes in glomerular podocytes; however, these effects were reversed with Shensu IV treatment. Compared with the control, the numbers of autophagosomes were markedly reduced in the model group, but not in the Shensu IV treatment group. Furthermore, the expression of p62 was significantly higher in the model group than in the controls, whereas the LC3-II/I ratio was significantly lower; however, these changes were not observed when Shensu IV was administered. The protective effects of Shensu IV were further confirmed in podocytes displaying puromycin-induced injury. Compared with control group, the expression of long non-coding RNA (lncRNA) H19, mTOR, p-mTOR, and p62 was significantly increased in the puromycin group, whereas that of distinct subgroup of the RAS family member 3 (DIRAS3) was significantly decreased, as was the LC3-II/I ratio. The opposite results were obtained for both shH19- and Shensu IV-treated cells. Collectively, our data demonstrated that Shensu IV can prevent glomerular podocyte injury in nephrotic rats and puromycin-treated podocytes, likely via promoting lncRNA H19/DIRAS3-regulated autophagy.

Atrazine-induced environmental nephrosis was mitigated by lycopene via modulating nuclear xenobiotic receptors-mediated response.

The burden and morbidity of environmental nephrosis is increasing globally. Atrazine (ATR) and degradation products in the environment are considered key determinants of nephrosis. However, the lack of highly effective treatments for environmental nephrosis creates an urgent need to better understand the preventive strategies and mechanisms. This study aimed to highlight the mechanism of ATR-induced environmental nephrosis and the chemoprotective potential of lycopene (LYC) against the renal injury and nephrosis. Male mice were treated with LYC (5 mg/kg) and/or ATR (50 mg/kg or 200 mg/kg) by gavage administration for 21 days. Histopathological changes and biochemical function, cytochrome P450 enzymes system (CYP450s), nuclear xenobiotic receptors (NXRs) response and the transcription of CYP isoforms (CYPs) were detected. ATR exposure caused the changes of the histopathological and biochemical function, activated the NXR response and disturbed the CYP450s homeostasis. Supplementary LYC significantly prevented ATR-induced nephrotoxicity and alleviated the alternation of histopathological and biochemical function via modulating the CYP450s homeostasis and the NXR response. The results demonstrated AHR, CAR, PXR, PPAR (α, γ), CYP1, CYP2, CYP3 and CYP4 superfamily play a vital role in LYC-ATR interaction. Our findings provide new evidence that ATR exposure can cause the environmental nephrosis via inducing the kidney injury. Supplementary LYC showed significant chemoprotective potential against ATR-induced renal injury and environmental nephrosis via regulating the NXR response and the CYP450s homeostasis.

Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis.

The highly conserved spalt (sal) gene family members encode proteins characterized by multiple double zinc finger motifs of the C2H2 type. Humans and mice each have four known Sal-like genes (SALL1-4 in humans and Sall1-4 in mice). Sall1 is known to have a crucial role in kidney development. To explore the significance of Sall1 in differentiated podocytes, we investigated podocyte-specific Sall1-deficient mice (Sall1 KOp°d°/p°d°) using a podocin-Cre/loxP system and siRNA Sall1 knockdown (Sall1 KD) podocytes. Under physiological conditions, Sall1 KOp°d°/p°d° mice exhibited no proteinuria during their lifetime, but foot-process effacement was detected in some of the podocytes. To elucidate the role of Sall1 in injured podocytes, we used an adriamycin (ADR)-induced model of nephrosis and glomerulosclerosis. Surprisingly, the expression of Sall1 was elevated in control mice on day 14 after ADR injection. On day 28 after ADR injection, Sall1 KOp°d°/p°d° mice exhibited significantly higher levels of proteinuria and higher numbers of sclerotic glomeruli. Differentiated Sall1 KD podocytes showed a loss of synaptopodin, suppressed stress fiber formation, and, ultimately, impaired directed cell migration. In addition, the loss of Sall1 increased the number of apoptotic podocytes following ADR treatment. These results indicated that Sall1 has a protective role in podocytes; thus, we investigated the endoplasmic reticulum stress marker GRP78. GRP78 expression was higher in ADR-treated Sall1 KOp°d°/p°d° mice than in control mice. Sall1 appeared to influence the expression of GRP78 in injured podocytes. These results suggest that Sall1 is associated with actin reorganization, endoplasmic reticulum stress, and apoptosis in injured podocytes. These protective aspects of Sall1 re-expression in injured podocytes may have the potential to reduce apoptosis and possibly glomerulosclerosis.

Sodium Bicarbonate-Ascorbic Acid Combination for Prevention of Contrast-Induced Nephropathy in Chronic Kidney Disease Patients Undergoing Catheterization.

BACKGROUND: Sodium bicarbonate and ascorbic acid have been proposed to prevent contrast-induced nephropathy (CIN). The present study evaluated the effect of their combined use on CIN incidence.Methods and Results:We prospectively enrolled 429 patients with chronic kidney disease (CKD: baseline estimated glomerular filtration rate <60 mL/min/1.73 m2) prior to elective coronary catheterization. CIN was defined as absolute (≥0.5 mg/dL) or relative (≥25%) increase in serum creatinine within 72 h. In the saline hydration (n=218) and combined sodium bicarbonate+ascorbic acid (n=211) groups, a total of 1,500-2,500 mL 0.9% saline was given before and after the procedure. In addition, the combination group received 20 mEq sodium bicarbonate and 3 g ascorbic acid i.v. before the procedure, followed by 2 g ascorbic acid after the procedure and a further 2 g after 12 h. There were no significant differences between the basic characteristics and contrast volume in the 2 groups. CIN occurred in 19 patients (8.7%) in the saline group, and in 6 patients (2.8%) in the combined treatment group (P=0.008). CONCLUSIONS: Combined sodium bicarbonate and ascorbic acid could prevent CIN following catheterization in CKD patients.

Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity.

Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.

Yi Qi Qing Re Gao formula ameliorates puromycin aminonucleoside-induced nephrosis by suppressing inflammation and apoptosis.

BACKGROUND: Yi Qi Qing Re Gao (YQQRG) formula is a traditional Chinese herbal medicine used to treat chronic nephritis. This study was designed to evaluate the underlying mechanism in the use of YQQRG formula to treat nephrosis induced by puromycin aminonucleoside (PAN). METHODS: Thirty-six male Wistar rats were randomly divided into 3 groups of 12 rats each: a sham group, a vehicle-treated PAN model group (PAN), and a group treated with YQQRG (PAN + YQQRG). The PAN model was established by a single intravenous injection of PAN at a dose of 40 mg/kg body weight; rats in the sham group received the same volume of saline. Twenty-four hour urinary protein was measured 0, 3, 5, 10, and 15 days after the injection. The rats were sacrificed on day 10 and day 15 and the serum lipid profile examined. The renal cortex of each rat was stained with periodic acid-Schiff reagent and the pathologic alterations and ultrastructural changes were examined by transmission electron microscopy. In situ cell apoptosis was detected by a terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) assay. Transcriptive levels of inflammatory markers and molecules associated with apoptosis were detected by a real-time polymerase chain reaction and expression of proteins was examined by either immunohistochemistry or Western blot analysis. RESULTS: YQQRG significantly decreased urinary protein level, and lowered serum lipid level. YQQRG also attenuated histologic lesions in the rat kidneys. Activation of inflammatory markers was largely restored by the administration of YQQRG. TUNEL assay showed that YQQRG decreased the number of apoptotic cells. Both mRNA and protein levels of caspase-3 were significantly reduced in the group treated with YQQRG, whereas expression of the Bcl-2 protein increased in the YQQRG group. CONCLUSIONS: YQQRG alleviated kidney injury in PAN-treated rats, possibly through anti-inflammatory and anti-apoptotic effects.

Effects of dietary salt restriction on renal progression and interstitial fibrosis in adriamycin nephrosis.

BACKGROUND/AIMS: Although high salt intake is thought to accelerate renal progression in proteinuric kidney disease, it is not known whether strict dietary salt restriction could delay renal inflammation and interstitial fibrosis. Here, we sought to answer this question in a rat model of adriamycin-induced nephrotic syndrome. METHODS: Adriamycin was administered via the femoral vein in a single bolus (7.5 mg/kg), and the rats were put on a sodium-deficient rodent diet. Rats with intact kidneys were studied for 5 weeks (experiment 1), and uninephrectomized rats were studied for 6 weeks (experiment 2). RESULTS: In experiment 1, restricting salt intake improved renal tubulointerstitial histopathology in adriamycin-treated rats. Immunohistochemical and immunoblot results additionally showed that restricting dietary salt lowered adriamycin-induced expression of osteopontin, collagen III, and fibronectin. In experiment 2, salt restriction improved adriamycin-induced azotemia, although it did not affect proteinuria or blood pressure. Dietary salt restriction also reduced adriamycin-induced infiltration of ED1-positive cells and the upregulated expression of osteopontin and α-SMA. Masson's trichrome and Sirius red staining revealed that salt restriction slowed Adriamycin-induced progression of renal interstitial fibrosis. Finally, qPCR revealed that adriamycin-induced expression of TNF-α, IκB-α, gp91(phox), p47(phox), and p67(phox) mRNA was blocked by salt restriction. CONCLUSION: Our findings demonstrate that strict dietary salt restriction delays the progress of renal inflammation and fibrosis in proteinuric kidney disease, most likely via relieving the reactive oxygen species-mediated NF-κB activation.

The RIP1-kinase inhibitor necrostatin-1 prevents osmotic nephrosis and contrast-induced AKI in mice.

The pathophysiology of contrast-induced AKI (CIAKI) is incompletely understood due to the lack of an appropriate in vivo model that demonstrates reduced kidney function before administration of radiocontrast media (RCM). Here, we examine the effects of CIAKI in vitro and introduce a murine ischemia/reperfusion injury (IRI)-based approach that allows induction of CIAKI by a single intravenous application of standard RCM after injury for in vivo studies. Whereas murine renal tubular cells and freshly isolated renal tubules rapidly absorbed RCM, plasma membrane integrity and cell viability remained preserved in vitro and ex vivo, indicating that RCM do not induce apoptosis or regulated necrosis of renal tubular cells. In vivo, the IRI-based CIAKI model exhibited typical features of clinical CIAKI, including RCM-induced osmotic nephrosis and increased serum levels of urea and creatinine that were not altered by inhibition of apoptosis. Direct evaluation of renal morphology by intravital microscopy revealed dilation of renal tubules and peritubular capillaries within 20 minutes of RCM application in uninjured mice and similar, but less dramatic, responses after IRI pretreatment. Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 (RIP1) kinase domain, prevented osmotic nephrosis and CIAKI, whereas an inactive Nec-1 derivate (Nec-1i) or the pan-caspase inhibitor zVAD did not. In addition, Nec-1 prevented RCM-induced dilation of peritubular capillaries, suggesting a novel role unrelated to cell death for the RIP1 kinase domain in the regulation of microvascular hemodynamics and pathophysiology of CIAKI.

Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease.

Two types of alternatively activated macrophages, M(2a) induced by IL-4/IL-13 and M(2c) by IL-10/TGF-ß, exhibit anti-inflammatory functions in vitro and protect against renal injury in vivo. Since their relative therapeutic efficacy is unclear, we compared the effects of these two macrophage subsets in murine adriamycin nephrosis. Both subsets significantly reduced renal inflammation and renal injury; however, M(2c) macrophages more effectively reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria than M(2a) macrophages. The M(2c) macrophages were also more effective than M(2a) in reduction of macrophage and CD4(+) T-cell infiltration in kidney. Moreover, nephrotic mice treated with M(2c) had a greater reduction in renal fibrosis than those treated with M(2a). M(2c) but not M(2a) macrophages induced regulatory T cells (Tregs) from CD4(+)CD25(-) T cells in vitro, and increased Treg numbers in local draining lymph nodes of nephrotic mice. To determine whether the greater protection with M(2c) was due to their capability to induce Tregs, the Tregs were depleted by PC61 antibody in nephrotic mice treated with M(2a) or M(2c). Treg depletion diminished the superior effects of M(2c) compared to M(2a) in protection against renal injury, inflammatory infiltrates, and renal fibrosis. Thus, M(2c) are more potent than M(2a) macrophages in protecting against renal injury due to their ability to induce Tregs.

A novel nuclear factor κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates puromycin aminonucleoside-induced nephrosis in mice.

BACKGROUND/AIMS: Minimal-change nephrotic syndrome (MCNS) is a kidney disease defined by selective proteinuria and hypoalbuminemia occurring in the absence of cellular glomerular infiltrates or immunoglobulin deposits. Recent observations suggest that nuclear factor κB (NF-κB) of podocyte is strongly associated with the development of proteinuria in MCNS. Dehydroxymethylepoxyquinomicin (DHMEQ) is a novel NF-κB inhibitor that potently inhibits DNA-binding activity of NF-κB, resulting in several therapeutic effects in various pathological conditions. We conducted this study to ask whether DHMEQ may ameliorate the nephrosis in mice induced by puromycin aminonucleoside (PAN), which is considered to be an animal model for MCNS. METHODS/RESULTS: Pretreatment with DHMEQ alleviated the proteinuria and reversed the serum abnormalities in mice nephrosis induced by 450 mg/kg of PAN. Increased serum interleukin-6 level in PAN-induced nephrosis was also completely suppressed by DHMEQ. Electron microscopic analyses of glo-meruli indicated that DHMEQ can inhibit the podocyte foot process effacement via blocking the translocation of podocyte NF-κB from cytoplasm to nucleus. CONCLUSIONS: These results suggest that DHMEQ can be a potential therapeutic agent for MCNS.

IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis.

IL-10/TGF-beta-modified macrophages, a subset of activated macrophages, produce anti-inflammatory cytokines, suggesting that they may protect against inflammation-mediated injury. Here, macrophages modified ex vivo by IL-10/TGF-beta (IL-10/TGF-beta Mu2) significantly attenuated renal inflammation, structural injury, and functional decline in murine adriamycin nephrosis (AN). These cells deactivated effector macrophages and inhibited CD4+ T cell proliferation. IL-10/TGF-beta Mu2 expressed high levels of the regulatory co-stimulatory molecule B7-H4, induced regulatory T cells from CD4+CD25- T cells in vitro, and increased the number of regulatory T cells in lymph nodes draining the kidneys in AN. The phenotype of IL-10/TGF-beta Mu2 did not switch to that of effector macrophages in the inflamed kidney, and these cells did not promote fibrosis. Taken together, these data demonstrate that IL-10/TGF-beta-modified macrophages effectively protect against renal injury in AN and may become part of a therapeutic strategy for chronic inflammatory disease.

Renoprotective effect of the L/N-type calcium channel antagonist cilnidipine on puromycin aminonucleoside-induced nephrosis in rats.

The renoprotective effect of cilnidipine ((+/-)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, CAS 132203-70-4), a L/N-type calcium channel antagonist, on puromycin aminonucleoside (PAN)-induced nephrosis was investigated in rats. In the Experiment I, rats were given an intravenous injection of PAN (70 mg/kg). Cilnidipine (3 mg/kg/day) and enalapril (CAS 75847-73-3, 5 mg/kg/day) were administered orally from 6 days after treatment with PAN (day 6) to day 26, and urinary analysis was performed on days 9, 15, 20 and 27. In the Experiment II, nephrosis was also induced by intravenous injection of PAN (70 or 100 mg/kg) in rats which were treated with cilnidipine and enalapril from days 6 to 10. Systolic blood pressure was measured on day 7 and urinary analysis was performed on day 10. On day 11, serum was collected and the kidneys were removed for immunofluorescence staining for nephrin and podocin proteins. In PAN-treated rats, the daily urinary protein excretion was dramatically elevated on day 5, reached a peak on day 9 and gradually returned to a normal level from days 15 to 27. Cilnidipine (3 mg/kg/ day) significantly suppressed the increase in proteinuria on day 9 and also improved the decrease in creatinine clearance without evident effect on the blood pressure. Furthermore, the elevations in serum total cholesterol and triglyceride tended to be suppressed by cilnidipine. The expression of nephrin and podocin proteins in PAN-treated rats showed the granular pattern in the glomeruli, while the intensity of staining seemed to be dependent on the urinary protein excretion level in the cilnidipine-treated rats. The results obtained in this study suggest a renoprotective effect of cilnidipine in PAN-induced nephrosis in rats.

[Relationship between glomerular nephrin expression and oxidative stress reaction in rats with adriamycin-induced nephrosis].

OBJECTIVE: It has been proposed that nephrotic syndrome is a consequence of an imbalance between oxidant and anti-oxidant activity. Nephrin plays an important role in maintaining glomerular filtration barrier. This study aimed to explore the relationship between the expression of glomerular nephrin and oxidative stress reaction in rats with adriamycin (ADR)-induced nephrosis, and the protection of prednisone and vitamin E against renal injuries. METHODS: Nephrosis was induced by single intravenous injection of ADR (5 mg/kg). The prednisone intervention group was administered with prednisone (10 mg/kg daily) between 1 and 4 weeks after ADR injection. The vitamin E intervention group received vitamin E of 20 mg/kg daily from 1 week before ADR injection till to 4 weeks after ADR injection. Control rats were intravenously injected with normal saline. After 7, 14, 21 and 28 days of ADR injection, the indexes of oxidative stress reaction of the renal cortex, malondialdehyde (MDA), superoxide dismutase (SOD) and total antioxidative capacity (T-AOC), were measured using the chemical chromatometry. The protein expression of glomerular nephrin was measured by immunohistochemistry. RESULTS: Prednisone or vitamin E treatment reduced urinary protein from 14 days to 28 days after ADR injection. MDA levels of renal cortex increased, while renal activities of SOD and T-AOC as well as nephrin protein contents decreased in untreated nephrosis group from 7 days after ADR injection compared with those in the control rats. Compared with the untreated nephrosis group, prednisone treatment resulted in an increase in nephrin protein contents 28 days after ADR injection; Vitamin E treatment decreased renal MDA levels and increased renal activities of SOD and T-AOC and nephrin protein contents 28 days after ADR injection. Nephrin staining showed a sable linear-like pattern along the capillary loops of glomerulus in the control rats. Nephrin staining presented a light tan discontinuous short linear-like or punctiform pattern along the capillary loops of glomerulus in the untreated ADR group. Prednisone or vitamin E treatment ameliorated abnormal expression of nephrin induced by nephrosis. Glomerular nephrin expression level was negatively correlated with renal MDA level and positively correlated with renal activities of SOD and T-AOC. CONCLUSIONS: A reduction of glomerular nephrin expression is closely related to oxidative stress reaction. Prednisone and vitamin E have protective effects against renal injuries induced by ADR in rats.

Determinants of amount of contrast utilized in patients undergoing percutaneous coronary procedures.

OBJECTIVE: To determine predictors of contrast amount during coronary angiography and percutaneous coronary intervention. BACKGROUND: Contrast-induced nephropathy is a leading cause of hospital-acquired acute renal insufficiency. During percutaneous coronary procedures, contrast amount is a major risk factor incriminated in development of contrast-induced nephropathy. METHODS: Demographic and procedural details were obtained for consecutive patients undergoing percutaneous coronary procedures between January 2002 and October 2005 (N=962, mean+/-standard error of contrast amount: 216.6+/-3.0 ml) at a tertiary care hospital. RESULTS: A significant difference (P value <0.05) in unadjusted mean contrast volume was observed between subgroups of percutaneous coronary intervention vs. coronary angiography, patients with a history of coronary artery bypass grafting, patients undergoing additional procedures and multivessel and multisite percutaneous coronary interventions. On General Linear Model analysis, independent predictors (beta coefficient, 95% confidence interval, P value) of increased contrast amount during percutaneous coronary procedures were history of coronary artery bypass grafting (44.4, 30.6-58.2, <0.001), type of coronary procedure (85.2, 73.4-97.0, <0.001 for percutaneous coronary intervention vs. coronary angiography), number of interventions and number of additional procedures performed. Among additional procedures, rotablation, intravascular ultrasound and Angiojet were associated with increased contrast use. No significant independent effect on the contrast amount was observed with percutaneous coronary intervention location (right coronary artery vs. left anterior descending artery vs. circumflex artery) site (ostial vs. proximal vs. mid vs. distal) of percutaneous coronary intervention or with interventions on chronic total occlusions on the contrast amount. CONCLUSION: Data from our study could guide the coronary angiographer in moderating the volume of contrast utilized as well as assist with the elective planning of complex therapeutic procedures.

Effects of dietary catechins on glucose tolerance, blood pressure and oxidative status in Goto-Kakizaki rats.

Effects of green tea catechins comprising EGCg, EGC, ECg, EC, GCg, GC, Cg, and C were determined on blood glucose tolerance and oxidative stress status in type 2 diabetic Goto-Kakizaki (GK) rats. GK rats fed the catechin-containing diet tended to maintain blood glucose and systolic blood pressure at lower levels in the latter stages of the feeding period of 76 d, compared to those not receiving dietary catechins (control group). The blood glucose tolerance test performed on days 48-49 showed that GK rats fed the catechins had lower blood glucose levels than GK rats not fed catechins during the 120 min after glucose loading. In catechin-fed rats, amounts of 8-OH dG and albumin excreted into the urine determined on days 71-72, and kidney ACE activity determined on day 76, were lower than those in control rats. From these results it is concluded that dietary catechins may be effective in delaying the progression of diabetes and the associated oxidative stress.

Protective effect of radical scavenger edaravone against puromycin nephrosis.

AIM: Recent studies have indicated that reactive oxygen species (ROS) play a role in the pathogenesis of glomerular injury leading to proteinuria in nephrotic syndrome. In the present investigation, we examined the effects of the radical scavenger edaravone administered at various time points to rats with puromycin nephrosis. MATERIALS AND METHODS: 35 Wistar rats were divided into five groups: treatment with puromycin aminonucleoside (PAN) alone, treatment with PAN followed by edaravone in the early period, treatment with PAN followed by edaravone administration in the late period, treatment with PAN and administration of edaravone for the whole experimental period, and untreated controls. On Days 3, 6 and 9, urinary protein excretion was measured. The levels of glomerular thiobarbituric acid-reactive substance (TBArs) were determined in all animals on Day 10. RESULTS: On Day 9, rats that had been administered edaravone showed reduced urinary protein excretion and reduced glomerular TBArs. In particular, edaravone administration in the late period, during which proteinuria was most acute, had the effect of reducing the severity of proteinuria. Glomerular TBArs were suppressed to the control level. Our results indicate that edaravone exerts a protective effect in the acute phase of PAN nephrosis when administered as antioxidant therapy at the onset of proteinuria. CONCLUSIONS: Edaravone can ameliorate urinary protein excretion after the onset of proteinuria in nephrotic syndrome.

Effect of cyclosporine and sirolimus on the expression of connective tissue growth factor in rat experimental chronic nephrotoxicity.

BACKGROUND/AIMS: Connective tissue growth factor (CTGF) is a pro-fibrotic growth factor that acts downstream of transforming growth factor (TGF)-beta. However, CTGF regulation remains unknown. We tried to determine the effect of two commonly used immunosuppressants, cyclosporine (CsA) and sirolimus (SRL), on CTGF expression in a model of chronic nephrotoxicity. METHODS: Adult Sprague-Dawley rats kept on a low-salt diet were treated daily for 4 weeks with vehicle (VH), SRL (0.3 mg/kg), CsA5 (5 mg/kg), CsA10 (10 mg/kg) or both CsA5 and SRL. CTGF and TGF-beta1 expressions were evaluated by Northern blot. Functional and histologic parameters in addition to number of apoptotic cells were determined. RESULTS: At 28 days, both CsA doses were capable of inhibiting CTGF mRNA expression to levels similar to control. On the other hand, SRL increased CTGF expression by 3.5-fold. However, addition of CsA to SRL completely reversed that trend and returned levels to control. The results were different for TGF-beta1, which was increased by both CsA and SRL and to a greater extent by the drug combination. CONCLUSION: Unlike TGF-beta, CTGF does not seem to play an important role in CsA-induced chronic nephrotoxicity. In addition, calcineurin-dependent pathways are likely involved in CTGF regulation.

Relaxin improves renal function and histology in aging Munich Wistar rats.

Administration of recombinant human relaxin (rhRLX) to conscious, chronically instrumented rats increases GFR and effective renal plasma flow (ERPF) and decreases effective renal vascular resistance (ERVR) with no significant change in mean arterial pressure. The Munich Wistar albino rat shows progressive chronic nephrosis with age and therefore was used to determine the functional and histologic consequences of rhRLX on matrix remodeling in the kidney of older rats. RLX-infused rats showed increased GFR and ERPF with decreased ERVR. Furthermore, in a double-blinded examination, the renal histology showed a significant decrease in glomerular and tubular collagen deposition in the rhRLX-infused aged rats. During short-term rhRLX administration (24 h), gelatinase activity was found to be essential for renal vasodilation and hyperfiltration. Surprisingly, after 20 d, improved renal function was insensitive to the inhibition of gelatinase activity, suggesting that collagen degradation in these rats had permanently altered the matrix of the renal vasculature. In conclusion, long-term administration of rhRLX improves renal function and ameliorates renal pathology in an aging rat model. The biphasic action of rhRLX on the kidney indicates that, acutely, the vessels dilate, causing increased filtration and renal blood flow with decreased vascular resistance as a result of upregulation of gelatinase activity. Subsequently, the renal vessels undergo alteration in supporting matrix, showing increased blood supply even in the face of acute matrix metalloproteinase inhibition, most likely as a result of the inhibitory properties of RLX on collagen production or increased collagen breakdown.

Gentamicin-induced nephrotoxicity and protective effect of caffeic acid phenethyl ester in rats.

The objective of this study was to investigate the beneficial effects of caffeic acid phenethyl ester (CAPE) on gentamicin (GM)-induced nephrotoxicity in Wistar rats. Twenty-one adult Wistar rats were divided into three groups as follows: control group, GM and GM + CAPE group. Control group rats were injected with 5% ethanol, GM group rats were treated with 100 mg/kg GM and GM + CAPE group were pretreated with 10 mumol/kg CAPE for 2 days, then exposed to GM at the same dose. Drug injections were applied for 12 days. Twenty-four hours after the last injection, rats were killed and kidneys were quickly removed. Tissue malondialdehyde (MDA) measurements and microscopic examination of kidneys were performed. In the GM group, significant increases in MDA levels were observed (P < 0.05). These changes were found to be normalized in the GM + CAPE group. Exposure to GM caused necrosis of tubular epithelial cells. Necrosis of tubules were found to be prevented by CAPE pretreatment. In conclusion, CAPE exerted an improvement on GM-induced nephrotoxicity, possibly, at least in part through inhibition of the production of oxygen free radicals that cause lipid peroxidation.