Long-Term Treatment with Empagliflozin Attenuates Renal Damage in Obese Zucker Rat.

INTRODUCTION: Empagliflozin, a known inhibitor of sodium-glucose cotransporter type 2 (SGLT2) decreases glucose reabsorption by the renal tubules and promotes glucose excretion into the urine. While the effectiveness of Empagliflozin in the management of hyperglycemia along with associated cardiovascular and all-cause mortality has been demonstrated previously, the therapeutic benefits associated with the long-term use of this drug in obese animals have yet to be investigated. METHODS: Male 5-week-old lean and obese Zucker rats were randomly assigned to one of the 4 groups- lean control, lean treated, obese control, obese treated and treated with either Empagliflozin (10 mg/kg BW / day) or placebo for 25 weeks to investigate the therapeutic effect of Empagliflozin. RESULTS: Empagliflozin treatment in the obese animals was associated with decreased body weight, attenuated the loss of F-actin from the renal tubules and improved renal structure and function. These changes in renal function were associated with significant improvements in the glucose tolerance, and decreased non-fasting circulatory levels of glucose, amylase, and other inflammatory markers including NGAL, cystatin C, and clusterin. CONCLUSION: Long-term use of Empagliflozin in diabetic obese Zucker rats is associated with improvements in glucose tolerance and decreased loss of renal structure and function.

Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats.

BACKGROUND: Hepatic ischemia reperfusion is one the main causes for graft failure following transplantation. Although, the molecular events that lead to hepatic failure following ischemia reperfusion (IR) are diverse and complex, previous studies have shown that excessive formation of reactive oxygen species (ROS) are responsible for hepatic IR injury. Cerium oxide (CeO2) nanoparticles have been previously shown to act as an anti-oxidant and anti-inflammatory agent. Here, we evaluated the protective effects of CeO2 nanoparticles on hepatic ischemia reperfusion injury. METHODS: Male Sprague Dawley rats were randomly assigned to one of the four groups: Control, CeO2 nanoparticle only, hepatic ischemia reperfusion (IR) group and hepatic ischemia reperfusion (IR) plus CeO2 nanoparticle group (IR+ CeO2). Partial warm hepatic ischemia was induced in left lateral and median lobes for 1h, followed by 6h of reperfusion. Animals were sacrificed after 6h of reperfusion and blood and tissue samples were collected and processed for various biochemical experiments. RESULTS: Prophylactic treatment with CeO2 nanoparticles (0.5mg/kg i.v (IR+CeO2 group)) 1 hour prior to hepatic ischemia and subsequent reperfusion injury lead to a decrease in serum levels of alanine aminotransaminase and lactate dehydrogenase at 6 hours after reperfusion. These changes were accompanied by significant decrease in hepatocyte necrosis along with reduction in several serum inflammatory markers such as macrophage derived chemokine, macrophage inflammatory protein-2, KC/GRO, myoglobin and plasminogen activator inhibitor-1. However, immunoblotting demonstrated no significant changes in the levels of apoptosis related protein markers such as bax, bcl2 and caspase 3 in IR and IR+ CeO2 groups at 6 hours suggesting necrosis as the main pathway for hepatocyte death. CONCLUSION: Taken together, these data suggest that CeO2 nanoparticles attenuate IR induced cell death and can be used as a prophylactic agent to prevent hepatic injury associated with graft failure.

Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats.

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500mg/kg, ip), an inhibitor of LTA(4) synthesis, 1h before NDPS (0.4mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD(4) receptor antagonist LY171883 (100mg/kg, po) was administered 0.5h before and again 6h after NDHS (0.1mmol/kg, ip) or 2-NDHSA (0.1mmol/kg, ip) or vehicle. Renal function was monitored for 48h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity.