Chronic kidney disease (CKD) is a global healthcare problem; however until now, there is no effective treatment that can stop its progression. In this study, we aimed to investigate the effect of empagliflozin, a sodium-glucose linked transporter-2 inhibitor (SGLTI) in a model of unilateral ureteric obstruction (UUO) in rats, as a model of progressive renal interstitial fibrosis in vivo and the possibility of inclusion of klotho protein. Rats were randomly divided into five groups: group 1: control group, group 2: UUO untreated group, group 3: prophylactic SGLTI treatment before UUO, group 4: immediate SGLTI treatment after UUO, and group 5: delayed SGLTI treatment (this group received distilled water 1 week after UUO then empagliflozin for 2 weeks). At the end of the experiment period, animals were sacrificed, and kidney fibrotic and inflammatory parameters were measured. Also kidney sections were examined histopathologically for CTGF expression. UUO resulted in renal dysfunction and fibrosis through upregulating inflammatory cascade (NF-κB-TLR4) as well as many fibrotic pathways (as TGF-β, αSMA, Wnt, CTGF, and fibronectin) with significant reduction in the klotho protein expression. We hypothesized that both prophylactic and immediate treatment with empagliflozin after UUO in rats exert more renoprotective effect in comparison with delayed treatment via enhancement of renal klotho expression and activity, for further investigations.

Doxorubicin (Dox)-induced cardiotoxicity constitutes the major adverse effect that limited its use. We investigated the possible protective effects of liraglutide on Dox-induced cardiotoxicity in rats. Rats were divided into the following groups: control group rats received normal saline [1 ml/kg, intraperitoneal (i.p.)]; doxorubicin group rats received doxorubicin (1.25 mg/kg, i.p.), four times per week for 4 weeks; and liraglutide group rats received doxorubicin (1.25 mg/kg, i.p.) four times per week for 4 weeks then received liraglutide (100 μg/kg, i.p) daily for 4 weeks. At the end of the study, animals were sacrificed and serum creatine kinase-MB (CK-MB) and troponin I levels were determined. Malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and caspase-3 levels of the heart were determined. Cardiac AMPK, phosphorylated-Akt, tissue growth factor-β1 (TGF-β1), and GSK3-β levels of the heart were determined. Hematoxylin and eosin (H&E) stained sections form the heart were examined as well as immunohistochemical sections for detection of Bcl-2 expression. Dox treatment increased serum level of troponin I and CK-MB while decreased SOD activity, decreased AMPK, and p-Akt cardiac levels with increased in MDA, IL-6, TNF-α,GSK-3b, TGFB1, and caspase-3 levels in the heart with inflammation and necrosis in cardiac histopathology with decreased Bcl-2. Treatment with liraglutide decreased troponin I and CK-MB while increased SOD activity, AMPK, p-Akt with decrements in MDA, IL-6, TNF-α, GSK-3β, TGF-β1, and caspase-3 levels with attenuation of inflammation and necrosis while increased Bcl-2 expression. Liraglutide may thus represent a new clinical tool for the treatment of Dox-induced cardiotoxicity.

We investigated the possible protective effects of pentoxifylline (PTX) and cilostazol on doxorubicin (Dox)-induced cardiotoxicity in rats. Rats are randomly assigned into: saline, Dox (I.P. 2.5 mg/kg every other day six injections over two weeks), Dox (I.P. 2.5 mg/kg every other day six injections over two weeks then PTX (50 mg/kg/day/oral), Dox (I.P. 2.5 mg/kg) every other day six injections over two weeks then cilostazol (50 mg/kg/day/oral). After 21 days these animals were sacrificed and serum CK-MB and troponin I levels were determined. Malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and caspase-3 levels also were determined. Heart sections were examinedhistopathologically. Treatment with PTX and cilostazol decreased troponin I and CK-MB while increased SOD activity with decrements in MDA, IL-6, TNF-, and caspase-3 levels with attenuation of the changes in cardiac histopathology. PTX and cilostazol exert protective effects against Dox-induced cardiotoxicity.

Many adipocytokines correlate with obesity and insulin resistance. We examined the effects of metformin, sitagliptin, and liraglutide in diabetic rats. Group 1: control normal (CN) rats received oral saline daily. Group 2: diabetic non-treated (DNT) rats were injected with streptozotocin (STZ) to get diabetic then after 72 h received oral saline daily. Group 3: rats were injected with STZ then after 72 h were treated with metformin (200 mg/kg) orally. Group 4: rats were injected with STZ then after 72 h received sitagliptin 6 mg/kg orally twice daily. Group 5: rats were injected with STZ then after 72 h were treated with liraglutide at a dose of 0.3 mg/kg every 12 h subcutaneous injection. After 8 weeks, body mass, fasting blood glucose, adipocytokines, and lipid profile were assessed. From the results, we concluded that the 3 drugs improved blood glucose and insulin resistance with correction of adipocytokines serum levels; however, the liraglutide-treated group was the only group that showed significant body mass reduction.

Ischemia-reperfusion (IR) injury constitutes the most important cause of primary dysfunction of liver grafts. In this study, we have addressed the possible hepatoprotective action of liraglutide against partial warm hepatic IR injury in male rats. Rats were randomly assigned into: sham, IR, and liraglutide-pretreated IR groups. Liraglutide was administered 50 μg/kg s.c. twice daily for 14 days, and then, hepatic IR was induced by clamping portal vein and hepatic artery to left and median lobes for 30 min followed by reperfusion for 24 h. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) activities were determined. Malondialdehyde (MDA) level, reduced glutathione (GSH) content, tumor necrosis factor-α (TNF-α), phosphoralated Akt (p-Akt), and caspase-3 levels of the liver were determined. Hematoxylin and eosin (H&E) stained sections from liver were examined as well as immunohistochemical sections for detection of Bcl-2 expression. IR injury increased ALT, AST, and GGT while decreased GSH and p-Akt with increase in MDA, TNF-α, and caspase-3 levels in the liver with necrosis and inflammatory cellular infiltration with decreased Bcl-2 expression. Pretreatment with liraglutide decreased ALT, AST, and GGT activities while increased glutathione content and Akt activation with decrements in MDA, TNF-α, and caspase-3 levels with attenuation of necrosis and inflammation while enhanced Bcl-2 expression in the liver. Liraglutide protects against IR injury of the liver through antiinflammatory and antioxidant actions as well as inhibition of apoptosis.