Protective effects of celecoxib on ischemia reperfusion-induced acute kidney injury: comparing between male and female rats.

OBJECTIVES: There is increasing evidence for the importance of gender in different diseases; however, the role of gender in response to treatments is still unknown. Therefore, this study investigated the impact of gender on the protective effects of celecoxib in ischemia reperfusion (IR)-induced acute kidney injury. MATERIALS AND METHODS: In this experimental study, rats were randomly divided into 6 groups (n=6): IR, sham and celecoxib groups of males and females. In IR groups, after orally receiving saline for 5 days, renal pedicles were clamped for 55 min and then kidneys were reperfused for 24 hr. In the sham groups, clamping of renal pedicles was not performed. In the celecoxib groups, 30 mg/kg celecoxib was given orally for 5 days before induction of ischemia. Plasma was collected to determine creatinine (Cr) and blood urea nitrogen (BUN). Kidney tissue samples were also stored for examining the histopathology and measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) activities. RESULTS: IR caused significant increases in plasma Cr (P<0.05), BUN (P<0.05) and renal histopathological damages in both genders. Also, induction of IR resulted in significant increase of MDA levels (P<0.05) and decrease of SOD activities (P<0.05) in the kidney in both genders. Celecoxib administration prevented the IR-induced functional, histopathological and oxidative changes in both genders by similar degrees. CONCLUSION: This study suggested that in similar pathological conditions, celecoxib improves renal function and histopathological damages and attenuates oxidative stress in both genders by the same degrees. These protective effects of celecoxib on IR-induced kidney injury are gender-independent.

Protective effects of hydrogen sulfide on chronic kidney disease by reducing oxidative stress, inflammation and apoptosis.

The current study aimed to examine the renoprotective effects of long-term treatment with sodium hydrosulfide (NaHS), a prominent hydrogen sulfide donor, in 5/6 nephrectomy animal model. Twenty-four rats were randomly divided into 3 groups including sham-operated group (Sham), 5/6-nephrectomized group (5/6 Nx), and NaHS-treated group (5/6Nx+NaHS). NaHS (30 micromol/l) was added twice daily into the drinking water and renal failure was induced by 5/6 nephrectomy. Twelve weeks after surgical procedure, blood pressure, creatinine clearance (CCr), urine concentration of neutrophil gelatinase associated lipocalin (NGAL) and tissue concentration of malondialdehyde (MDA), superoxide dismutase (SOD), as well as renal morphological changes, apoptosis (cleaved caspase-3) and inflammation (p-NF-κB) were measured. Five-sixth nephrectomy induced severe renal damage as indicated by renal dysfunction, hypertension and significant histopathological injury which were associated with increased NGAL and MDA levels, oxidant/antioxidant imbalance, decreased SOD activity and CCr and also overexpression of p-NF-κB and cleaved caspase-3 proteins. Instead, NaHS treatment attenuated renal dysfunction through reduction of NGAL concentration, hypertension, CCr, oxidant/antioxidant imbalance, inflammation and apoptosis. These findings suggest that long term NaHS treatment can be useful in preventing the progression of CKD by improving oxidant/antioxidant balance and reducing inflammation and apoptosis in the kidney.

Resuscitative therapy with erythropoietin reduces oxidative stress and inflammatory responses of vital organs in a rat severe fixed-volume hemorrhagic shock model.

Hemorrhagic shock (HS) still has a high mortality rate and none of the known resuscitative regimens completely reverse its adverse outcomes. This study investigated the effects of different models of resuscitative therapy on the healing of organ damage in a HS model. Male Wistar rats were randomized into six groups: Sham, without HS induction; HS, without resuscitation; HS+Blood, resuscitation with the shed blood; HS+Blood+NS, resuscitation with blood and normal saline; HS+Blood+RL, resuscitation with blood and Ringer's lactate; EPO, erythropoietin was added to the blood and RL. Blood and urine samples were obtained 3 h after resuscitation. Kidney, liver and brain tissue samples were harvested for multiple organ failure evaluation. Survival rate was the highest in the Sham, EPO and HS+Blood+RL groups compared to others. Plasma creatinine concentration, ALT, AST, urinary NAG activity and renal NGAL mRNA expression significantly increased in the HS+Blood+RL group compared to the Sham group. There was a significant increase in tissue oxidative stress markers and pro-inflammatory cytokines in HS+Blood+RL group compared to the Sham rats. EPO had more protective effects on multiple organ failure compared to the HS+Blood+RL group. EPO, as a resuscitative treatment, attenuated HS-induced organ damage. It seems that it has a potential to be attractive for clinical trials.

Involvement of neuronal pathways in the protective effects of hindlimb perconditioning during renal ischemia.

Remote ischemic perconditioning (RPEC) is a therapeutic intervention that has been demonstrated to reduce renal ischemia/reperfusion (I/R) injury. However, the underlying renal protective mechanism remains unclear. The present study hypothesized that RPEC may utilize neural pathways to transfer the protective signal from the perconditioned hindlimb to the kidney. Following a right nephrectomy, rats were randomly allocated into five groups (n=6). The sham group underwent the surgical protocol only. In all other groups, the left renal pedicle was clamped for 45 min and reperfused for 24 h. The I/R control group then underwent 45 min ischemia and 24 h reperfusion (I/R) with no more intervention but the I/R-NR control group underwent the ischemia and reperfusion followed by left femoral nerve (FN) and sciatic nerve (SN) resection. The RPEC group underwent ischemia and reperfusion followed by four cycles of 5 min occlusions of the left femoral artery and 5 min reperfusion. Finally, the RPEC-NR group underwent ischemia and reperfusion followed by left FN and SN resection. Following 24 h, renal functional indices, plasma blood urea nitrogen (BUN) and creatinine (Cr) levels, urinary N-acetyl-ß-glucosaminidase (NAG) release and histopathological changes were assessed. Compared with the sham group, ischemia and reperfusion in the sham and I/R control groups resulted in renal dysfunction, indicated by significantly increased levels of BUN and Cr. This was accompanied by increased urinary NAG activity and morphological damage observed in control groups. In the RPEC group, renal histology and function were significantly improved compared with the control groups. However, FN and SN resection eliminated the protection of the kidney, which was induced by RPEC. In conclusion, remote hindlimb ischemic perconditioning reduced renal I/R injury in the rat kidney in a manner that potentially involves a neural pathway.

Ameliorative Effect of Recombinant Human Erythropoietin and Ischemic Preconditioning on Renal Ischemia Reperfusion Injury in Rats.

BACKGROUND: Ischemia-reperfusion (IR) injury is one of the most common causes of renal dysfunction. There is increasing evidence about the role of the reactive oxygen species (ROS) in these injuries and endogenous antioxidants seem to have an important role in decreasing the renal tissue injury. OBJECTIVES: The aim of this study was to compare the effect of recombinant human erythropoietin (EPO) and ischemic preconditioning (IPC) on renal IR injury. MATERIALS AND METHODS: Twenty four male Wistar rats were allocated into four experimental groups: sham-operated, IR, EPO + IR, and IPC + IR. Rats were underwent 50 minutes bilateral ischemia followed by 24 hours reperfusion. Erythropoietin (5000 IU/kg, i.p) was administered 30 minutes before onset of ischemia. Ischemic preconditioning was performed by three cycles of 3 minutes ischemia followed by 3 minutes reperfusion. Plasma concentrations of urea and creatinine were measured. Kidney samples were taken for reactive oxidative species (ROS) measurement including superoxide dismutase (SOD) activity, glutathione (GSH) contents, and malondialdehyde (MDA) levels. RESULTS: Compared to the sham group, IR led to renal dysfunction as evidenced by significantly higher plasma urea and creatinine. Treatment with EPO or IPC decreased urea, creatinine, and renal MDA levels and increased SOD activity and GSH contents in the kidney. CONCLUSIONS: Pretreatment with EPO and application of IPC significantly ameliorated the renal injury induced by bilateral renal IR. However, both treatments attenuated renal dysfunction and oxidative stress in kidney tissues. There were no significant differences between pretreatment with EPO or application of IPC.

Angiotensin II in paraventricular nucleus contributes to sympathoexcitation in renal ischemia-reperfusion injury by AT1 receptor and oxidative stress.

BACKGROUND: To investigate the effect of angiotensin II (Ang II) in the hypothalamic paraventricular nucleus (PVN) on renal ischemia-reperfusion (IR) injury and to assay the role of renal sympathetic nerve activity (RSNA). METHODS: A cannula was inserted into the right side PVN in Sprague-Dawley rats for microinjection of Ang II (3, 30, and 300 ng); Ang II AT1 receptor antagonist, losartan (0.3 µg); and the superoxide dismutase (SOD) mimetic, tempol (20 nmol) before right side nephrectomy. After 1 wk, renal IR injury was induced by clamping the left renal artery for 45 min, and then reperfusion for 3 or 24 h. The extent of renal damage was determined by evaluation of renal functional indices. RSNA was recorded in all groups. Oxidative stress indices (SOD activity and malondialdehyde levels) were assayed in the PVN. RESULTS: Microinjection of pharmacologic doses of Ang II into the PVN exaggerated renal IR injury, increased RSNA and oxidative stress in the PVN dose dependently. The effects of Ang II (3 ng) was prevented by pretreatment with losartan into the PVN. Furthermore, the deleterious effects of Ang II on renal IR injury, RSNA, and oxidative stress were abolished by pretreatment with tempol. CONCLUSIONS: These results indicate that the PVN is a responsive site for central Ang II increment damage in renal ischemia-reperfusion injury. We suggested the central effects of Ang II in the PVN on renal IR injury are mediated by AT1 receptors and oxidative stress in the PVN, and the peripheral effects by a sympathetic pathway.

Enhancement of renal oxidative stress by injection of angiotensin II into the paraventricular nucleus in renal ischemia-reperfusion injury.

This study was designed to investigate whether microinjection of angiotensin II (Ang II) into the hypothalamic paraventricular nucleus (PVN) in renal ischemia-reperfusion (IR) injury has any effect on renal oxidative stress and damage through renal sympathetic nerve activity (RSNA). One week before the induction of left renal IR injury, right nephrectomy was performed and a cannula was placed into the right PVN. Rats were then distributed among 4 groups (n = 6); Sham, IR, IR + Ang II, and IR + Ang II + losartan. Renal IR injury was induced by clamping the left renal artery for 45 min followed by 24 h reperfusion. Losartan (0.3 µg) and Ang II (3 ng) were microinjected into the PVN at 20 min and 10 min, respectively, before the induction of IR injury. Ang II increased plasma creatinine, urinary NAG activity, and histological changes, and enhanced RSNA compared with the IR group (p < 0.05). Ang II increased malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD) activity in the kidney compared with IR injury. Losartan caused a reduction in plasma creatinine, urinary NAG activity, histological changes, renal sympathetic nerve activity (RSNA), and renal MDA levels, and increased renal SOD activity compared with the IR group (p < 0.05). These data demonstrated that increased RSNA activity, via microinjection of Ang II into the PVN, exaggerated renal IR injury by inducing oxidative stress in the kidney.

Anti-epileptogenic and antioxidant effect of Lavandula officinalis aerial part extract against pentylenetetrazol-induced kindling in male mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Repeated application of Lavandula officinalis (L. officinalis) has been recommended for a long time in Iranian traditional medicine for some of nervous disorders like epilepsy and dementia. However, there is no available report for the effect of chronic administration of Lavandula extract in development (acquisition) of epilepsy. Therefore, this study was designed to investigate the anti-epileptogenic and antioxidant activity of repeated administration of Lavandula officinalis extract on pentylenetetrazol (PTZ) kindling seizures in mice model. MATERIALS AND METHODS: Lavandula officinalis was tested for its ability (i) to suppress the seizure intensity and lethal effects of PTZ in kindled mice (anti-epileptogenic effect), (ii) to attenuate the PTZ-induced oxidative injury in the brain tissue (antioxidant effect) when given as a pretreatment prior to each PTZ injection during kindling development. Valproate (Val), a major antiepileptic drug, was also tested for comparison. RESULTS: Val and Lavandula officinalis extract showed anti-epileptogenic properties as they reduced seizure score of kindled mice and PTZ-induced mortality. In this regard, Lavandula officinalis was more effective than Val. Both Lavandula officinalis and Val suppressed brain nitric oxide (NO) level of kindled mice in comparison with the control and PTZ group. Meanwhile, Lavandula officinalis suppressed NO level more than Val and Lavandula officinalis also decreased brain MDA level relative to PTZ group. CONCLUSION: This is the first report to demonstrate NO suppressing and anti-epileptogenic effect of chronic administration of Lavandula officinalis extract on acquisition of epilepsy in PTZ kindling mice model. In this regard, Lavandula officinalis extract was more effective than Val, possibly and in part via brain NO suppression.