Browsing by Author "Rodrigues-Santos, P."
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- Serum and renal tissue markers of nephropathy in rats under immunosuppressive therapy: cyclosporine vs sirolimusPublication . Sereno, J.; Parada, B.; Rodrigues-Santos, P.; Lopes, P.; Carvalho, E.; Vala, Helena; Teixeira-Lemos, E.; Alves, R.; Figueiredo, A.; Mota, A.; Teixeira, F.; Reis, F.Cyclosporin (CsA) has been progressively replaced by other drugs with putatively fever side effects, including nephrotoxicity and hypertension. Sirolimus (SRL) is one of the main options for management of kidney transplant patients in the post-CsA era. It shows identical efficacy with apparently less cardiorenal side effects than CsA. However, doubts remain concerning the mechanisms of putative renoprotection by SRL as well as the best serum and/or tissue markers for nephropathy, as assessed in this study employing CsA- and SRL-treated rats. Three groups (n = 6) were treated orally during a 6-week protocol: control (vehicle); CsA (5 mg/kg body weight per day Sandimmun Neoral); SRL (1 mg/kg body weight per day Rapamune). Blood pressure and heart rate were assessed with a "tail cuff". Renal dysfunction and morphology were characterized using serum creatinine and blood urea nitrogen (BUN) levels as well as hematoxylin and eosin and periodic acid Schiff staining, respectively. We examined serum concentrations of interleukin (IL)-2, IL-1β, high-sensitivity C-reactive protein, tumor necrosis factor TNF-α, and vascular endothelial growth factor and kidney mRNA expression of interleukin-1β (IL-1β), tumor protein 53 (TP53), mammalian target of rapamycin (mTOR) and proliferating cell nuclear antigen (PCNA), as well as markers of lipid peroxidation in the kidney and serum. Both CsA and SRL induced significant increases in systolic and diastolic blood pressure, but only CsA caused tachycardia. CsA-treated rats also displayed increased serum creatinine and BUN levels, accompanied by mild renal lesions, which were almost absent among SRL-treated rats, which presented hyperlipidemic and hyperglycemic profiles. CsA-induced nephrotoxicity was accompanied by kidney overexpression of inflammatory and proliferative mRNA markers (IL-1β, mTOR and PCNA), which were absent among SRL group. In conclusion, the antiproliferative and antifibrotic character of SRL may explain its less nephrotoxic profile. Renal over expression of mTOR in the CsA-treated group, associated with renal dysfunction and structural damage, reinforces the potential beneft of SRL as a strategy to reduce CsA-evoked nephrotoxicity.
- Sitagliptin ameliorates kidney lesions in a rat model of type 2 diabetes due to anti-inflammatory and anti-apoptotic effectsPublication . Marques, C.; Mega, C.; Gonçalves, A.; Rodrigues-Santos, P.; Vala, Helena; Teixeira-Lemos, E.; Teixeira, F.; Fontes-Ribeiro, C.; Reis, F.; Fernandes, R.Objective: This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of T2DM, the Zucker Diabetic Fatty (ZDF) rat. Methods: ZDF rats (aged 20 weeks) were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia, HbA1c, urea and creatinine levels were monitored. Kidney glomerular and tubulointerstitial lesions were assessed using a semiquantitative rating. Kidney mRNA and/or protein content of DPP-IV, GLP-1, TNF-α, IL-1β, BAX, Bcl-2 and Bid were evaluated by RT-PCR and/or WB. Protein distribution was evaluated by immunohistochemistry. Results: Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c, and prevented the diabetes-induced increase in DPP-IV levels and decrease in GLP-1 levels. Sitagliptin ameliorated diabetes-induced glomerular atrophy and IFTA, and the increased urea levels. Sitagliptin decreased kidney IL-1β and TNF-α, and prevented the increase of BAX/Bcl-2 ratio and Bid protein levels, which indicates protective effects against inflammation and pro-apoptotic state in the kidney of diabetic rats, respectively. Conclusion: Sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and anti-apoptotic properties.
- Sitagliptin prevents aggravation of endocrine and exocrine pancreatic damage in the Zucker Diabetic Fatty rat - focus on amelioration of metabolic profile and tissue cytoprotective propertiesPublication . Mega, C.; Vala, Helena; Rodrigues-Santos, P.; Oliveira, J.; Teixeira, F.; Fernandes, R.; Reis, F.; Lemos, ETBACKGROUND: The purpose of this study was to investigate some of the possible mechanisms underlying the protective effects of a dipeptidyl peptidase IV (DPP-IV) inhibitor, sitagliptin, on pancreatic tissue in an animal model of type 2 diabetes mellitus (T2DM), the Zucker Diabetic Fatty(ZDF) rat, focusing on glycaemic, insulinic and lipidic profiles, as well as, on apoptosis, inflammation, angiogenesis and proliferation mediators. METHODS: Male obese diabetic ZDF (fa/fa) rats, aged 20 weeks, were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks and compared to untreated diabetic and lean control littermates. Metabolic data was evaluated at the beginning and at the end of the treatment, including glycaemia, HbA1c, insulinaemia, HOMA-beta and TGs. Endocrine and exocrine pancreas lesions were assessed semiquantitatively by histopathological methods. Pancreas gene (mRNA) and protein expression of mediators of apoptotic machinery, inflammation and angiogenesis/proliferation (Bax, Bcl2, IL-1β, VEGF, PCNA and TRIB3) were analyzed by RT-qPCR and/or by immunohistochemistry. RESULTS: Sitagliptin treatment for 6 weeks (between 20 and 26 week-old) was able to significantly (p < 0.001) ameliorate all the metabolicparameters, by preventing the increase in blood glucose and in serum TGs contents (16.54% and 37.63%, respectively, vs untreated), as well as, by preventing the decrease in serum insulin levels and in the functional beta cells capacity accessed via HOMA-beta index (156.28% and 191.74%, respectively, vs untreated). Sitagliptin-treated diabetic rats presented a reduced pancreas Bax/Bcl2 ratio, suggestive of an antiapoptotic effect; in addition, sitagliptin was able to completely reduce (p < 0.001) the pancreas overexpression of IL-1β and TRIB3 found in the untreated diabeticanimals; and promoted a significant (p < 0.001) overexpression of VEGF and PCNA. CONCLUSION: In this animal model of obese T2DM (the ZDF rat), sitagliptin prevented β-cell dysfunction and evolution of pancreatic damage. The protective effects afforded by this DPP-IV inhibitor may derive from improvement of the metabolic profile (viewed by the amelioration of glucose and TGs levels and of insulin resistance) and from cytoprotective properties, such as antiapoptotic, anti-inflammatory, pro-angiogenic and pro-proliferative.