Renal Protection of In Vivo Administration of Tempol in Streptozotocin-Induced Diabetic Rats

Luan, Jiajie; Li, Weiping; Han, Juan; Wen, Zhang; Gong, Huiyu; Ma, Rong

doi:10.1254/jphs.12002fp

Cited by 22 publications

(19 citation statements)

References 54 publications

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“…On the basis of these findings, pitavastatin appeared to have anti-oxidation independent action. On the other hand, Luan et al [35] reported that 6-week treatment with tempol in diabetic rats significantly ameliorated the renal dysfunction and pathological changes in glomeruli, and our findings were inconsistent with their results. We cannot clearly explain the reason of these discrepancies, but our 3-week study period was the half time of theirs, which might cause these discrepant results.…”

Section: Discussioncontrasting

confidence: 99%

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

Ohigashi

Imai²,

Toba³

et al. 2016

Pharmacology

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Background/Aims: Podocytes injury is involved in the development of diabetic nephropathy. This study was designed to confirm the reno- and podocyte-protective effects of pitavastatin in diabetic rats and clarify its mechanisms. Methods: Wistar rats were divided into 4 treatment groups: control, streptozotocin (STZ; 55 mg/kg)-induced diabetes, STZ with pitavastatin (10 mg/kg/day), and STZ with tempol (1 mmol/l). Results: STZ-induced diabetic rats exhibited increases in urinary protein excretion and plasma creatinine, and a decrease in creatinine clearance. Pitavastatin significantly improved these parameters without reducing cholesterol levels, whereas tempol did not. The treatment with STZ-enhanced renal fibrosis, mesangial proliferation, transforming growth factor (TGF)-β, MCP-1 and suppressed Rho in association with decrement of bone morphogenetic protein (BMP)-7 expression in renal cortex. Moreover, STZ decreased podocyte related factors, podocin and nephrin, and BMP-7 in podocytes. Pitavastatin significantly ameliorated all these indices. On the other hand, improvement by tempol was found only in TGF-β, MCP-1 and histological changes. Conclusion: Pitavastatin exhibited reno- and podocyte-protective effects accompanied by BMP-7 preservation and Rho suppression.

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Section: Discussioncontrasting

confidence: 99%

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

Ohigashi

Imai²,

Toba³

et al. 2016

Pharmacology

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“…Increased PCOs in the kidney of SHADR group was associated with a significant reduction in the antioxidant enzyme activities of kSOD and kGSH-Px. These results were consistent with the findings described by others in diabetic rats [11], and ADR-induced nephropathy models [22,28–30]. Taking into account that peroxynitrite when acts as an oxidant produces nitrite and hydroxide ion rather than isomerizing to nitrate [33], we hypothesized that the increased nitrite production in the kidney of SHADR and the reduced level of nitrate that we observed compared to SHC, indicated an elevated level of peroxynitrite induced protein oxidation in this group, thus in conditions of reduced kidney antioxidant defense contributed to the deterioration of renal structure and function in this model of proteinuric nephropathy.…”

Section: Discussionsupporting

confidence: 94%

“…The alterations in renal function in SHR with ADR nephropathy, as noticed by the development of massive proteinuria in this study, were also accompanied by a significant reduction of SOD and GSH-Px activities in the kidney. The above findings are consistent with those previously reported in diabetic and ADR-induced nephropathy [11,28–30]. Because ADR accumulates mainly in the kidney [31], and given that the kTBARS remained unchanged after ADR treatment in the present study, similar to results obtained by Zima et al in Wistar rats [32] or in BALC/c mice with early ADR nephropathy one week after application of 10mg/kg [28], we performed protein carbonyl test to find out whether protein carbonilation, an irreversible process induced in vivo by all types of reactive oxygen and nitrogen species including peroxynitrite, and followed by loss of enzymatic activities, loss of ligand binding properties, increased susceptibility to proteolytic activities, aggregation, and modification in the transcriptional activities [7], could participate in ADR-induced nephropathy in SHR.…”

Section: Discussionsupporting

confidence: 94%

Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy

et al. 2016

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Oxidative stress has been widely implicated in both hypertension and chronic kidney disease (CKD). Hypertension is a major risk factor for CKD progression. In the present study we have investigated the effects of chronic single tempol (membrane-permeable radical scavenger) or losartan (angiotensin II type 1 receptor blocker) treatment, and their combination on systemic oxidative status (plasma thiobarbituric acid-reactive substances (pTBARS) production, plasma antioxidant capacity (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid, pABTS), erythrocyte antioxidant enzymes activities) and kidney oxidative stress (kTBARS, kABTS, kidney antioxidant enzymes activities), kidney function and structure in spontaneously hypertensive rats (SHR) with the early course of adriamycin-induced nephropathy. Adult SHR were divided into five groups. The control group received vehicle, while the other groups received adriamycin (2 mg/kg, i.v.) twice in a 21-day interval, followed by vehicle, losartan (L,10 mg/kg/day), tempol (T,100 mg/kg/day) or combined T+L treatment (by gavage) during a six-week period. Adriamycin significantly increased proteinuria, plasma lipid peroxidation, kidney protein oxidation, nitrite excretion, matrix metalloproteinase-1 (MMP-1) protein expression and nestin immunostaining in the kidney. Also, it decreased kidney antioxidant defense, kidney NADPH oxidase 4 (kNox4) protein expression and abolished anti-inflammatory response due to significant reduction of kidney NADPH oxidase 2 (kNox2) protein expression in SHR. All treatments reduced protein-to-creatinine ratio (marker of proteinuria), pTBARS production, kidney protein carbonylation, nitrite excretion, increased antioxidant capacity and restored kidney nestin expression similar to control. Both single treatments significantly improved systemic and kidney antioxidant defense, bioavailability of renal nitric oxide, reduced kMMP-1 protein expression and renal injury, thus retarded CKD progression. Losartan improved blood pressure, as well as tubular injury and restored anti-inflammatory defense by reverting kNox2 expression to the control level. Interestingly, tempol was more successful in reducing systemic oxidative stress, proteinuria, kMMP-1 and glomerulosclerosis. However, combined treatment failed to overcome the beneficial effects of single treatments in slowing down the progression of ADR-induced nephropathy in SHR.

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“…However, tempol has previously been shown to reduce urine flow in diabetic animals. 38 The reduced cortical RBF in diabetic kidneys, despite unaltered total RBF, may relate to a technical issue when using the laser Doppler technique on kidneys with different stages of hypertrophy. It is also unlikely that augmented oxygen delivery, secondary to increased hematocrit caused by the HIF activation, is a major contributor to the mitigated intrarenal hypoxia, because intrarenal pO 2 in the diabetic kidney mainly is determined by QO 2 .…”

Section: Discussionmentioning

confidence: 99%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

176

145

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Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetesinduced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

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Renal Protection of In Vivo Administration of Tempol in Streptozotocin-Induced Diabetic Rats

Cited by 22 publications

References 54 publications

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

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