Gentamicin-induced Kidney Injury Research Articles

The anti-inflammatory properties of green tea extract protect against gentamicin-induced kidney injury

We assessed in vivo the protective effects and underlying antioxidant and anti-inflammatory properties of dry green tee extract (GTE) on glomerular and tubular kidney function and structure in an experimental model of gentamicin (GEN)-induced nephrotoxicity. Wistar rats were divided into four groups and treated daily for 10 days. The control group received distilled water; the GTE group received 20 μg/g body weight (BW) GTE by gavage; the GEN group received 100 mg/g BW GEN intraperitoneally; and the GEN+GTE group received GTE and GEN simultaneously, as described above. At the beginning and end of treatment, the serum creatinine, fractional excretion of sodium and potassium, and plasma heme oxygenase (HO)-1 levels and oxidative stress (OS) were assessed. At the end of the experiment, kidney fragments were collected for histological evaluation and immunohistochemical studies of cyclooxygenase (COX)-2 and nuclear factor (NF)kB. The levels of interleukin (IL)-1b, IL-4, IL-6, IL-10 and monocyte chemotactic protein (MCP)-1 were measured in kidney tissue. The results showed that GTE attenuated significantly kidney structural injury and prevented GEN-induced kidney functional injury (glomerular and tubular function). GTE significantly attenuated the kidney tissue increase of the proinflammatory mediators NF-kB, COX2, IL-1b and MCP-1 and significantly increased the kidney expression of the anti-inflammatory cytokines IL-6 and IL-10. However, GTE did not prevent OS increase in GEN-treated animals. In conclusion, GTE protected against GEN nephrotoxicity, likely due to direct blockade of the inflammatory cascade, which might had occurred independently of its antioxidant effect.

Eucalyptol regulates Nrf2 and NF-kB signaling and alleviates gentamicin-induced kidney injury in rats by downregulating oxidative stress, oxidative DNA damage, inflammation, and apoptosis

Gentamicin, an aminoglycoside antibiotic, is nowadays widely used in the treatment of gram-negative microorganisms. The antimicrobial, anti-inflammatory, and antioxidant activities of eucalyptol, a type of saturated monoterpene, have been reported in many studies. The aim of this study was to examine the possible effects of eucalyptol on gentamicin-induced renal toxicity. A total of 32 rats were divided into 4 groups; Control (C), Eucalyptol (EUC), Gentamicin (GEN), and Gentamicin + Eucalyptol (GEN + EUC). In order to induce renal toxicity, 100 mg/kg gentamicin was administered intraperitoneally (i.p.) for 10 consecutive days in the GEN and GEN + EUC groups. EUC and GEN + EUC groups were given 100 mg/kg orally of eucalyptol for 10 consecutive days. Afterwards, rats were euthanized and samples were taken and subjected to histopathological, biochemical, immunohistochemical, and real-time PCR examinations. The blood urea nitrogen (BUN) and creatinine (CRE) levels were significantly decreased in the GEN + EUC group (0.76 and 0.69-fold, respectively) compared to the GEN group. The glutathione peroxidase (GPx) and catalase (CAT) activities were significantly increased in the GEN + EUC group (1.35 and 2.67-fold, respectively) compared to the GEN group. In GEN group, Nuclear factor kappa B (NF-kB), Interleukin 1-beta (IL-1β), Inducible nitric oxide synthase (iNOS), Tumor necrosis factor-α (TNF-α), Caspase-3, 8-Hydroxy-2′-deoxyguanosine (8-OHdG) and Nuclear factor erythroid 2–related factor (Nrf2) expression levels were found to be quite irregular. GEN + EUC group decreased the expressions of NF-kB, IL-1β, iNOS, TNF-α, Caspase-3, and 8-OHdG (0.55, 0.67, 0.54, 0.54, 0.63 and 0.67-fold, respectively), while it caused increased expression of Nrf2 (3.1 fold). In addition, eucalyptol treatment ameliorated the histopathological changes that occurred with gentamicin. The results of our study show that eucalyptol has anti-inflammatory, antioxidative, antiapoptotic, nephroprotective, and curative effects on gentamicin-induced nephrotoxicity.

Cannabidiol interacts with the FXR/Nrf2 pathway and changes the CB1/CB2 receptors ratio in gentamicin-induced kidney injury in rats.

Gentamicin-induced nephrotoxicity was used as an experimental model of kidney disease. The present study was performed to assess the therapeutic role of cannabidiol (CBD) against gentamicin-induced renal damage. Forty two male Wistar rats were randomly allocated into 6 groups (n=7), including: (1) Control, (2) Vehicle, (3) Gentamicin-treated group (100 mg/kg/day) for 10 days (GM), (4-6) 3 Gentamicin-CBD-treated groups (2.5, 5, and 10 mg/kg/day) for 10 days (GM+CBD2.5, GM+CBD5, GM+CBD10). Serum levels of BUN and Cr, renal histology as well as real-time qRT-PCR were used to investigate the pattern of changes at different levels. Gentamicin increased serum BUN and Cr (P<0.001), down-regulation of FXR (P<0.001), SOD (P<0.05) and up-regulation of CB1 receptor mRNA (P<0.01). Compared to the control group, CBD at 5 decreased (P<0.05) and at 10 mg/kg/day increased the expression of FXR (P<0.05). Nrf2 expression in CBD groups was increased (P<0.001 vs. GM). The expression of TNF-α compared to the control and GM groups, was significantly increased in CBD2.5 (P<0.01) and CBD10 (P<0.05). Compared to the control, CBD at 2.5 (P<0.01), 5 (P<0.001) and 10 (P<0.001) mg/kg/day significantly increased the expression of CB1R. Up-regulation of CB1R in the GM+CBD5, was significantly higher (P<0.05) than the GM group. Compared to the control group, the most significant increase in CB2 receptor expression was observed at CBD10 (P<0.05). CBD particularly at 10 mg/kg/day might be of significant therapeutic benefit against such renal complications. Activating the FXR/Nrf2 pathway and counteracting the deleterious effects of CB1 receptors via CB2 receptors scale-up could be part of the protective mechanisms of CBD.

Oxymatrine Alleviates Gentamicin-Induced Renal Injury in Rats.

Gentamicin is an aminoglycoside antibiotic commonly used to treat Gram-negative bacterial infections that possesses considerable nephrotoxicity. Oxymatrine is a phytochemical with the ability to counter gentamicin toxicity. We investigated the effects and protective mechanism of oxymatrine in rats. The experimental groups were as follows: Control, Oxymatrine only group (100 mg/kg/d), Gentamicin only group (100 mg/kg/d), Gentamicin (100 mg/kg/d) plus Oxymatrine (100 mg/kg/d) group (n = 10). All rats were treated for seven continuous days. The results indicated that oxymatrine alleviated gentamicin-induced kidney injury, and decreased rats’ kidney indices and NAG (N-acetyl-beta-d-glucosaminidase), BUN (blood urea nitrogen) and CRE (creatine) serum levels. The oxymatrine-treated group sustained less histological damage. Oxymatrine also relived gentamicin-induced oxidative and nitrative stress, indicated by the increased SOD (superoxidase dismutase), GSH (glutathione) and CAT (catalase) activities and decreased MDA (malondialdehyde), iNOS (inducible nitric oxide synthase) and NO (nitric oxide) levels. Caspase-9 and -3 activities were also decreased in the oxymatrine-treated group. Oxymatrine exhibited a potent anti-inflammatory effect on gentamicin-induced kidney injury, down-regulated the Bcl-2ax and NF-κB mRNAs, and upregulated Bcl-2, HO-1 and Nrf2 mRNAs in the kidney tissue. Our investigation revealed the renal protective effect of oxymatrine in gentamicin-induced kidney injury for the first time. The effect was achieved through activation of the Nrf2/HO-1 pathways. The study underlines the potential clinical application of oxymatrine as a renal protectant agent for gentamicin therapy.

L-cysteine protective effects against platelet disaggregation and echinocyte occurrence in gentamicin-induced kidney injury.

Gentamicin (GM) is an aminoglycoside antibiotic that induces nephrotoxicity. GM also causes necrosis of cells in the renal proximal tubules, resulting in acute tubular necrosis, followed by acute renal failure. Morphological alteration of blood cells, leukocytes and platelets count, as well as biochemical effects of L-cysteine (Cys) and antibiotic gentamicin, in clinically healthy male Wistar rats, were studied. Rats were divided into four groups: control (injected with 0.9% saline i.p.), GM (80mg/kg b.w.; gentamicin injected i.p.), Cys-GM (100mg/kg b.w.; L-cysteine and 80mg/kg b.w. gentamicin injected i.p.), and Cys-GM-Cys (administered double dosage of 100mg/kg b.w. L-cysteine and 80mg/kg b.w. gentamicin i.p.). Biochemical and hematological analyses were performed on blood samples taken six days after treatments. Total proteins, albumin concentration and A/G ratio were significantly lower in experimental groups. Cholesterol, triglycerides, urea, and creatinine concentrations were significantly higher in relation to control. GM-induced lymphocytopenia, thrombocytopenia and neutrophilia. Echinocytosis and platelet disaggregation were found in all GM-treated animals. GM caused renal injury which indirectly led to erythrocyte abnormalities, changes in platelet aggregation, decreased protein fractions, and increased lipid and nitrogen components. The results suggest that GM-induced renal injury leads to significant biochemical changes in blood plasma, erythrocyte membrane impairment which can consequently cause anemia. Therefore, Cys might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced renal injury and blood cell disorders.

Celecoxib has Preventive and Therapeutic Benefits against Nephrotoxicity Caused by Gentamicin in Mice

It's crucial to comprehend the impact of oxidative stress and pro-inflammatory cytokines in the gentamicin-induced kidney injury mechanism. Celecoxib was administered orally either before or after intraperitoneal therapy with gentamicin in mice. The serum levels of creatinine (SCr), blood urea nitrogen (BUN), IL-6, and TNF-α were measured by ELISA test, as well as the levels of the kidney tissue malondialdehyde (MDA), and glutathione (GSH) were also estimated spectrophotometrically. The renal expression of nuclear factor-κB (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase 2 (COX-2) mRNAs were evaluated by qPCR. Histopathological evaluation and Immunohistochemical examination of kidney NF-κB, IL-6, and COX-2 were also, performed. Celecoxib successfully prevented gentamicin-induced kidney damage as indicated by reducing blood BUN, SCr, and tissue MDA levels and increasing renal tissue GSH levels as well as lowering the blood IL-6 and TNF-α in comparison to mice received gentamicin. Furthermore, celecoxib has inhibited COX-2, NF-κB, IL-6, and TNF-α expression in the renal tissue. It is noteworthy that celecoxib therapy after gentamicin administration brought about substantially the same results as celecoxib treatment before gentamicin injection in mice. Our results showed the role of celecoxib as a therapeutic tool for gentamicin-induced nephrotoxicity as well as raised its beneficial prophylactic role in this medical challenge by attenuating oxidative stress and inflammation.

Gentamicin-Induced Acute Kidney Injury in an Animal Model Involves Programmed Necrosis of the Collecting Duct.

Gentamicin is a potent aminoglycoside antibiotic that targets gram-negative bacteria, but nephrotoxicity limits its clinical application. The cause of gentamicin-induced AKI has been attributed mainly to apoptosis of the proximal tubule cells. However, blocking apoptosis only partially attenuates gentamicin-induced AKI in animals. Mice treated with gentamicin for 7 days developed AKI, and programmed cell death pathways were examined using pharmacologic inhibitors and in RIPK3-deficient mice. Effects in porcine and murine kidney cell lines were also examined. Gentamicin caused a low level of apoptosis in the proximal tubules and significant ultrastructural alterations consistent with necroptosis, occurring predominantly in the collecting ducts (CDs), including cell and organelle swelling and rupture of the cell membrane. Upregulation of the key necroptotic signaling molecules, mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), was detected in gentamicin-treated mice and in cultured renal tubule cells. In addition, gentamicin induced apical accumulation of total and phosphorylated MLKL (pMLKL) in CDs in mouse kidney. Inhibiting a necroptotic protein, RIPK1, with necrostatin-1 (Nec-1), attenuated gentamicin-induced necrosis and upregulation of MLKL and RIPK3 in mice and cultured cells. Nec-1 also alleviated kidney inflammation and fibrosis, and significantly improved gentamicin-induced renal dysfunction in mice. Furthermore, deletion of RIPK3 in the Ripk3-/- mice significantly attenuated gentamicin-induced AKI. A previously unrecognized role of programmed necrosis in collecting ducts in gentamicin-induced kidney injury presents a potential new therapeutic strategy to alleviate gentamicin-induced AKI through inhibiting necroptosis.

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs.

ABSTRACTThe clinical use of gentamicin over prolonged periods is limited because of dose and time-dependent nephrotoxicity, in which intracellular oxidative stress and heightened inflammation have been implicated. Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. The aim of this study was to determine changes in autophagy in response to the antioxidant N-acetylcysteine (NAC), via its effects on oxidative stress, inflammation, apoptosis, and renal function, following treatment with gentamicin in mini pigs. Adult mini pigs were divided into isotonic saline solution, gentamicin, and gentamicin plus NAC combination treatment groups. Gentamicin-induced histopathological changes, including inflammatory cell infiltration and tubular necrosis, were attenuated by NAC. NAC ameliorated the gentamicin-induced decreases in the levels of autophagy-related proteins, such as LC3 (microtubule-associated protein 1 light chain 3), PINK1 (phosphatase and tensin homologue deleted on chromosome10-induced kinase 1), phospho-parkin, AMBRA1 (activatingmolecule in Beclin 1-regulated autophagy), p62/SQSTM1 (sequestosome protein 1), and polyubiquitinated protein aggregates. NAC also caused a significant reduction in oxidative damage markers, including 4-hydroxy-2-nonenal, protein carbonyls, γ-H2AX (gamma histone variant H2AX), and 8-hydroxy-2′-deoxyguanosine, in gentamicin-treated animals. These data show that the protective effects of NAC might be related, at least in part, to a reduced inflammatory response, as observed in animals treated with both gentamicin and NAC. These results suggest that autophagy could be a new therapeutic target for preventing gentamicin-induced kidney injury, and that NAC might ameliorate gentamicin-induced nephrotoxicity by autophagy.

Precise Monitoring of Drug-Induced Kidney Injury Using an Endoplasmic Reticulum-Targetable Ratiometric Time-Gated Luminescence Probe for Superoxide Anions.

Drug-induced acute kidney injury (AKI), caused by renal drug metabolism, has been considered to be a major barrier in drug development and clinical treatment. Among various drugs, anticancer drugs, cisplatin, and aminoglycoside antibiotic gentamicin, are known to be able to induce excessive or unfolded accumulation of proteins in the endoplasmic reticulum (ER) of cells, leading to ER stress. Meanwhile, reactive oxygen species (ROS) are formed, and superoxide anion (O2•-), the first produced ROS, is a key species to induce the AKI. Due to the lack of appropriate tools, the early diagnosis of AKI induced by cisplatin, gentamicin, or other drugs is still a crucial challenge. Herein, we report a lanthanide complex-based ER-targetable luminescence probe for O2•-, ER-(4'-trifluoromethanesulfonyloxy-2,2':6',2''-terpyridine-6,6''-diyl)bis(methylenenitrilo)tetrakis (aceticacid) (NFTTA)-Eu3+/Tb3+, for the sensitive monitoring of drug-induced AKI via mapping the generation of O2•- in live cells and laboratory animals. Using this probe coupled with the ratiometric time-gated luminescence (RTGL) imaging technique, the changes of O2•- level in the ER of live cells induced by different stimuli were precisely monitored. More importantly, the substantial increases in O2•- levels were observed in the cisplatin- and gentamicin-induced kidney injury of mice. In addition, the protective effects of l-carnitine (LC) and epigallocatechin-3-gallate (EGCG) against cisplatin- and gentamicin-induced nephrotoxicity were visualized and elucidated for the first time. The results demonstrated the potential of ER-NFTTA-Eu3+/Tb3+ for examining and monitoring O2•- in drug-induced AKI and for providing a diagnosis and treatment of nephrotoxicity diseases.

RENOPROTECTIVE EFFECT OF MELATONIN IN CONDITIONS OF ACUTE KIDNEY INJURY AND ALTERED PINEAL GLAND ACTIVITY

INTRODUCTION: Melatonin is a promising therapeutic agent due to its multiple beneficial effects, wide availability and relatively high safety. As melatonin acts as a chronobiotic agent, its adequate production by the pineal gland allows for adaptation to environmental changes, while disturbances in melatonin secretion are associated with health disorders. The renoprotective effect of exogenous melatonin was established on different experimental models of acute kidney injury (AKI), while the influence of the altered pineal gland activity on the efficacy of melatonin treatment has not been investigated. &#x0D; OBJECTIVES: The aim of this research was to study the renoprotective potential of melatonin in conditions of aminoglycoside-induced AKI against the background of pineal hypo- and hyperfunction.&#x0D; METHODS: Nonlinear mature white rats (n=40) were randomly divided into 5 groups. Animals from the I (Control), and II (AKI) group were kept under the natural light regimen. Pineal hypofunction was simulated in rats from the III group by maintenance under conditions of constant light at 500 lux (24.00 light : 0.00 darkness) for 7 days. Pineal hyperfunction was simulated in rats from the IV group by maintenance under conditions of constant darkness (0.00 light : 24.00 darkness). Toxic AKI (II-IV groups) was induced by daily administration of gentamicin at a dose of 80 mg/kg for 6 days. Animals from the III-IV groups were injected daily with melatonin at a dose of 5 mg/kg. 24 h after the last injection biochemical and histological examination was performed. For the statistical analysis SPSS 17.0 software was used.&#x0D; RESULTS: Nephrotoxicity of gentamicin caused significant (p&lt;0.05) functional changes and structural alterations to the rat kidneys. Treatment with melatonin in conditions of gentamicin-induced kidney injury significantly limited the degree of damage to renal tissue and prevented a critical reduction in kidney function, confirming a protective effect of melatonin. At the same time, significant (p&lt;0.05) differences between the indices of the III and IV group allow us to state, that treatment with exogenous melatonin on the background of endogenous melatonin deficiency was less effective in comparison to the administration of melatonin in conditions of pineal hyperfunction.&#x0D; CONCLUSION: Melatonin ameliorates gentamicin-induced kidney injury by the limitation of histopathological changes in kidney tissue and the preservation of kidney function. Pre-existing deficiency of endogenous melatonin decreases the resistance of kidneys to the damaging action of the toxin and lessens the protective effect of the exogenous melatonin. Alternatively, in rats with increased pineal gland activity and melatonin production, co-treatment with exogenous melatonin more effectively protects the kidney from gentamicin-induced structural and functional changes and prevents the development of renal failure.

Effect of fatty acids from ethanol extract of Moringa oleifera seeds on kidney function impairment and oxidative stress induced by gentamicin in rats

Gentamicin, an aminoglycoside drug, used for the treatment of Gram-negative bacterial infections. Despite its potency against bacterial infections, its clinical use is limited owing to nephrotoxicity effect. However, the study investigated the nephroprotective effect of fatty acids from ethanolic extract of Moringa oleifera seeds (EEMOS) against gentamicin-induced kidney injury in rats. Forty-five male Wistar rats, 100–160 g, were divided into 5 groups as follows: Group 1 (control), 5 rats, received 0.2 ml/100 g/day of propylene glycol orally for 28 days. Group 2, 10 rats, received 100 mg/kg/day (i.p) of gentamicin (GENT) for 8 days. Group 3–5, 10 rats each, treated with EEMOS orally for 28 days at graded doses of 100, 200 and 400 mg/kg respectively after GENT treatment. Twenty four after treatment, five rats from each group were sacrificed. The remaining 5 rats were sacrificed after 2 weeks recovery period from the drugs. The result showed that GENT elicited polyuria, elevated plasma creatinine, urea, and lower plasma electrolytes and creatinine clearance levels. Measurements of 24 h urinary output demonstrated marked decrease in creatinine and potassium levels in the GENT-treated group, whereas sodium level remain unchanged. Also, GENT caused significant decrease in superoxide dismutase and an increase in malondialdehyde levels in the kidney of the rats. Histopathological examination revealed evidence of necrosis of the kidney. Treatment with EEMOS significantly ameliorated the alterations caused by GENT in the plasma, urine and kidney homogenate of the rats. Hence, the mono- and poly-unsaturated fatty acids present in EEMOS were responsible for its renoprotective ability.

Nephroprotective influence of ademetionine on the functional state of rats kidneys in conditions of gentamicin-induced kidney injury

Nephroprotective influence of ademetionine on the functional state of rats kidneys in conditions of gentamicin-induced kidney injury

Telbivudine attenuates gentamicin-induced kidney injury in rats.

Nephrotoxicity has been associated with nucleos(t)ide analogues other than telbivudine (LdT). This study investigated the potential effects of LdT and lamivudine (LAM) on renal function in an experimental rat model of gentamicin-induced acute nephrotoxicity. A total of 28 healthy Wistar albino rats were randomly divided into four experimental groups: negative control; positive control (PC); LdT; and LAM. Nephrotoxicity was induced by gentamicin in the LdT, LAM and PC groups. LdT and LAM were administered to two groups for 6 weeks starting on the ninth day. Blood samples were collected weekly and cystatin C levels were measured by ELISA. Animals were sacrificed on the 50th day and the kidneys were removed for histological examination. Serum cystatin C levels differed significantly between the LdT and LAM groups (P <0.007) and between the LdT and PC groups (P <0.001). Renal function was significantly improved in the LdT group at the start of antiviral treatment on Day 8 and at the end of treatment on Day 50 (P = 0.001 and 0.007). Glomerular injury, acute tubular necrosis and total injury score were significantly reduced in the LdT group relative to the PC and LAM groups upon histopathological examination. LdT was associated with significant improvements in renal function as measured by biochemical and histopathological methods. The acute kidney injury model data should be supported by clinical studies to suggest that LdT treatment may have advantages for patients with underlying chronic kidney disease receiving chronic hepatitis B treatment.

Nephroprotective effect of Rudgea viburnoides (Cham.) Benth leaves on gentamicin-induced nephrotoxicity in rats

RelevanceRudgea viburnoides, popularly known as "congonha-de-bugre” or “erva de bugre”, is used in folk medicine as hypotensive, blood depurative, anti-rheumatic, diuretic and in the treatment of kidney and bladder pain. AimBased on the popularly acclaimed nephron-protective effect of R. viburnoides, we investigated, using rats, the protective effect of this plant extract on gentamicin-induced kidney injury. Material and methodsUrinary volume, water and food intakes were assessed in adult male Wistar rats (naive or gentamicin-induced model of nephrotoxicity) treated with R. viburnoides extract. Also blood and kidney samples were collected for further laboratory and histological analyses. ResultsR. viburnoides leaves extract improved renal function. It also improved the renal function impairments caused by gentamicin-induced nephrotoxicity, as revealed by glomerular filtration rate, urine output and proteinuria. ConclusionR. viburnoides exert renoprotective effect, which may support its popular use for renal diseases treatment.

Ocimum gratissimum Ameliorates Gentamicin-Induced Kidney Injury but Decreases Creatinine Clearance Following Sub-Chronic Administration in Rats.

The effects of aqueous extract of Ocimum gratissimum leaf (AOGL) on the renal function of rats with gentamicin-induced nephrotoxicity were investigated. This study involved the use of forty five (45) adult male Wistar rats (housed in separate metabolic cages) such that graded doses of OAGL were administered to the experimental groups (p.o.) for 28 days after exposure to gentamicin toxicity (100 mg/kg i.p.) for 1 week. At the end of the study, comparisons of some indices of renal function as well as antioxidant status (GSH and TBARS) were made between the control, toxic and AOGL-treated groups at P < 0.05. The result showed that gentamicin treatment caused significant increase (P < .05) in urine output, urea, creatinine, total protein, relative kidney weight, and TBARS, as well as significant decrease (P < .05) in urine creatinine and GSH levels. Post-treatment with graded doses of AOGL caused significant increase in food consumption, GSH, urine, and plasma creatinine, as well as significant decrease (P < .05) in relative kidney weight, TBARS, and urine total protein. There was an appreciable difference in the kidney histology of the AOGL-treated groups when compared with the toxic control. Hence, the extract has therapeutic potential in the management of gentamicin-induced kidney injury, although a risk profile of renal dysfunction is not unlikely from 28 days of administration as evident by the decrease in creatinine clearance.

Treatment with methanolic extract of Ocimum gratissimum (Linn.) leaf reversibly normalizes urine protein-creatinine ratio in Wistar rat model of gentamicin-induced kidney injury

Background : Due to its rapid onset of action, high antibacterial efficacy and low cost, gentamicin (GEN) is still been used (particularly in underdeveloped and developing countries) despite its nephrotoxic antibiotic effects. Experimental ethno-botanical evaluations are imperative in a world with increasing incidence of kidney injury; a condition that is expensive to treat or manage. Aim : Effects of methanolic extract of Ocimum gratissimum (Linn.) leaf (MOGL) on urine proteincreatinine ratio (UPC) was determined in rats with GEN-induced kidney injury. Methods : This study involved the use of 50 rats such that graded doses of MOGL (100, 200 and 400 mg/kg p.o.) were administered following 8 days exposure to GEN (100 mg/kg i.p) and comparison were made against the control, toxic, 2 weeks and 4 weeks MOGL treatment groups at p <0.05. Results : GEN induced nephrotoxicity as depicted by significant perturbations in plasma and urine levels of creatinine and total protein (p <0.05); significantly lowered creatinine clearance and abnormal elevations of UPC as well as deleterious alterations of the kidney antioxidant system (GSH and TBARS) (p <0.05). Histopathological examination showed glomerular atrophy, formation of densely eosinophilic/ colloid cast within the tubules and severe loss of cellular constituents in the medullary interstitium. When compared with the control, these conditions were significantly normalized after 2 week MOGL treatment (p <0.05) with a deleterious reversal from normalcy at 4 week MOGL treatment (p <0.05). Conclusion : This study substantiated that MOGL has therapeutic potentials that becomes deleterious after sub-chronic administration in rat model of GEN-induced kidney injury. Key words : Gentamicin, renal function test, Ocimum gratissimum, urine protein-creatinine ratio, creatinine clearance, antioxidant system

Rhizoma smilacis glabrae protects rats with gentamicin-induced kidney injury from oxidative stress-induced apoptosis by inhibiting caspase-3 activation

Ethnopharmacological relevanceRhizoma smilacis glabrae (RSG), which is mild-natured and tastes sweet or bland, has pharmacological action of eliminating dampness, detoxifying, and ensuring that joints were healthy and supple in traditional Chinese medicine. Aim of the studyTo discuss the protective effect of RSG on gentamicin (GM)-induced kidney injury in rats and its regulatory mechanisms of oxidative stress-induced apoptosis by inhibiting caspase-3 activation. Materials and methodsA total of 40 Sprague–Dawley (SD) rats were randomly divided into 5 groups: control group, model group, and RSG low, middle, and high dose groups (0.75，1.5，3gkg−1). Six hours after intramuscular GM injections, rats in the model group were given distilled water by intragastric administration, and rats in the 3 RSG intervention groups were given different dosages of RSG water-extracts. Twenty-four hours after the last administration, blood and kidney samples were collected to test for biochemical indexes of kidney injury, oxidative stress, histopathological defects, apoptosis rate, and caspase-3 protein expression to assess the protective effect of RSG water-extracts against GM-induced kidney injury. ResultsCompared with the model group, serum TP and ALB levels were significantly higher (P<0.05), and BUN, CRE, and UA levels were significantly lower (P<0.05) in the 3 RSG intervention groups. In kidney tissues, SOD, CAT, and GSH levels increased significantly (P<0.05), while MDA level decreased significantly (P<0.05). Total apoptosis rate dropped markedly (P<0.01), and the protein expressions of caspase-3 increased, while expressions of activated caspase-3 decreased. Histopathological analysis showed shrinkage of kidney cells reduced with appearance of complete kidney structure and decrease in activated caspase-3 expressions in impaired renal tubules decreased. Among the 3 RSG intervention groups, the middle dose group (1.5gkg−1) showed the best protective effect. ConclusionsRSG water-extracts had protective effects against GM-induced kidney injury in rats, and its mechanism of action was related to oxidative stress-induced apoptosis by inhibiting caspase-3 activation.

Organic Cation Transporter 2 Overexpression May Confer an Increased Risk of Gentamicin-Induced Nephrotoxicity.

Nephrotoxicity is a relevant limitation of gentamicin, and obese patients have an increased risk for gentamicin-induced kidney injury. This damage is thought to depend on the accumulation of the drug in the renal cortex. Obese rats showed substantially higher levels of gentamicin in the kidney than did lean animals. This study characterized the role of organic cation transporters (OCTs) in gentamicin transport and elucidated their possible contribution in the increased renal accumulation of gentamicin in obesity. The mRNA and protein expression levels of the organic cation transporters Oct2 (Slc22a2) and Oct3 (Slc22a3) were increased in kidney samples from obese mice fed a high-fat diet. Similarly, OCT2 (∼2-fold) and OCT3 (∼3-fold) showed increased protein expression in the kidneys of obese patients compared with those of nonobese individuals. Using HEK293 cells overexpressing the different OCTs, human OCT2 was found to transport [(3)H]gentamicin with unique sigmoidal kinetics typical of homotropic positive cooperativity (autoactivation). In mouse primary proximal tubular cells, [(3)H]gentamicin uptake was reduced by approximately 40% when the cells were coincubated with the OCT2 substrate metformin. The basolateral localization of OCT2 suggests that gentamicin can enter proximal tubular cells from the blood side, probably as part of a slow tubular secretion process that may influence intracellular drug concentrations and exposure time. Increased expression of OCT2 may explain the higher accumulation of gentamicin, thereby conferring an increased risk of renal toxicity in obese patients.

Establishment of Simple and Routine Methods in Early Diagnosis of Gentamicin-Induced Kidney Injury Based on a Rat Model.

The changes in biomarkers of gentamycin- (GM-) induced kidney injury have been studied by using simple and routine methods and also assessed the efficacy and utility of these routine biomarkers in early diagnosis. Eighty Sprague-Dawley (SD) rats were randomly divided into 4 groups: three experimental groups treated with different GM dosages (4, 20, and 100 mg·kg−1) and a control group. The experimental groups were given intramuscular GM injections once daily for 14 days, and the control group was given intramuscular sterile water. Blood and urine samples were collected on treatment days 1, 3, 7, and 14 to test for total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (CRE), uric acid (UA), pH, specific gravity (SG), proteins (PRO), and cells in urinary sediment. Histopathology and kidney coefficient were performed on excised kidney specimens. The result indicated that serum CRE, BUN, and TP, urine PRO, and urinary hyaline casts and low-transitional epithelium showed an immediate and highly sensitive response to kidney injury, and the combined diagnosis with the above methods could be used in early diagnosis. Particularly, the process of the test was simple and quick, no special equipment, so it is more suit for primary medical institution.

Protective effects of metformin on renal tubular cells.

Dear Editor, Recently, we conducted a preclinical investigation to find the ameliorative properties of metformin on renal biochemical and histologic alterations of gentamicin-induced kidney damage in male Wistar rats (1). In this investigation, attenuation of gentamicin-induced acute kidney injury was found. Likewise, Taheri et al. conducted a study on the effects of metformin on renal tubular cells after unilateral ischemia reperfusion in rats’ kidney. They observed that metformin provided kidney protection against ischemia and reperfusion-induced injury (2). They concluded that metformin has tissue-protective effect through activation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (2). More recently we conducted a study on 70 male Wistar rats to test the efficacy of coadministrating garlic extract and metformin in prevention of gentamicin-induced renal tubular damage in Wistar rats (3). The result of this study showed that metformin, garlic juice, or their combination had both curative and protective effects on gentamicin-induced kidney injury. In addition, Kim et al. conducted a study using metformin for diabetic rats for 17 weeks and found that treatment of diabetic rats with metformin had restored podocyte loss. They suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by metformin through the repression of oxidative injury. They proposed that diabetes-induced podocyte loss in diabetic nephropathy could be reduced by metformin (4). Kim et al. found that the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was decreased in the kidney of diabetic rats and metformin could restore its modification (4). Diabetic nephropathy is one of the most important complications of diabetes mellitus (5-11) and metformin has been broadly used for the treatment of type 2 diabetes (12). Thus, the suggestion of Baradaran et al. further attests our results and those by Taheri et al., which stated metformin protects against tubular injury by restoring the biochemical alterations and modulation of oxidative stress on the tubules (2, 3). Furthermore, according to the study of Kim et al. metformin protects podocytes in diabetic nephropathy (4). On the other hand, there is also tubular cell injury in diabetic nephropathy due to glycosuria (12-18). These findings can more potentiate the clinical use of metformin in the prevention of diabetic nephropathy. Previously, Morales et al. showed that gentamicin-induced renal tubular damage was attenuated by metformin (17). It is evident that metformin treatment significantly attenuates the increase in malondialdehyde and total reactive oxygen species generation and restores both enzymatic and nonenzymatic antioxidants to their physiologic levels (18, 19). These findings advocate the use of metformin in diabetes due to its protective effect on kidney beyond its blood regulatory effects. In fact, it is reasonable to illuminate three different actions of metformin including blood sugar regulatory property, renal tubular cell protection by acting as an effective antioxidant, and finally, protective effect on diabetic nephropathy through saving the podocytes (4, 18, 19). Hence, patients with diabetes might benefit from all of these three distinct protective properties (4, 18, 19). In this regard, more experimental or clinical studies are recommended to improve our knowledge regarding the kidney protective properties of metformin.