Saudi Cultural Missions Theses & Dissertations
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Item Restricted Investigating the direct effects of SGLT2 inhibitors on kidney proximal tubule functions(Univeristy of Pittsbugh, 2025) Albalawy, Wafaa N; Weisz, Ora ABeyond glycemic control, sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of sodium/proton exchanger 3 (NHE3) leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule cells to determine the direct effects of SGLT2i on Na+-dependent fluid transport and endocytic uptake in this nephron segment. Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug. Canagliflozin acutely inhibited surface NHE3 activity, consistent with a direct effect, but did not affect endosomal pH or NHE3 phosphorylation. In addition, canagliflozin rapidly and selectively inhibited mitochondrial complex I activity. Inhibition of mitochondrial complex I by metformin recapitulated the effects of canagliflozin on endocytosis and fluid transport, whereas modulation of down- stream effectors AMPK and mTOR did not. Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake. We conclude that canagliflozin selectively suppresses Na+-dependent fluid transport and albumin uptake in PT cells via direct inhibition of NHE3 and of mitochondrial function upstream of the AMPK/mTOR axis. These additional targets of canagliflozin contribute significantly to reduced PT Na+-dependent fluid transport in vivo.8 0Item Restricted Does Using Empagliflozin Reduce Hospitalization for Heart Failure and Angina in People With Diabetes? A Systematic Review(2023-05-02) Alrefaee, Manal Ibrahim; Khan, EhsanBackground Current statistics show that there are over 422 million people with diabetes around the world, and these numbers are in continuous increase (Lin et al 2020). The presence of type 2 diabetes mellitus increases the incidence of cardiovascular diseases (Leon & Thomas 2015). There is an increase trend towards using SGLT2 (Sodium Glucose Cotransporter 2) inhibitors, including empagliflozin, in the treatment of people with diabetes as the have shown beneficial effects in improving glucose control and cardiovascular events. Objectives To examine whether empagliflozin decreases hospitalizations for heart failure or unstable angina for people with type 2 diabetes mellitus (T2DM). Selection method The included studies compared using empagliflozin, 25 mg/10 mg, with placebo, no treatment. Only randomized controlled trials selected. Participants were people ≥18 years old with type 2 diabetes mellitus. Method The preferred method for conducting this systematic review was the Cochrane Handbook for Systematic Reviews (2022). The search for study was carried out through EMBASE database, PubMed, and Cochrane from 2014 to 2022. The search strategy was the PICO, (P) stands for Population, (I) Intervention, (C) Comparison, and (O) Outcome. The selected studies were assessed for quality using CASP (Critical Appraisal Skills Programme) tool. The risk of bias was also assessed using the Cochrane Risk of Bias tool (RoB2). The study search, the quality assessment and risk of bias examination all conducted by one author. Main results Four studies were retrieved for this systematic review. The studies compared using empagliflozin, 25 mg or 10 mg, with placebo, no treatment. Hospitalizations for heart failure were significantly lower in intervention groups, there is no significant difference in all-cause hospitalization, and the as no significant difference in hospitalization for unstable angina between the two groups. Conclusion Provided the notable control of diabetes status, using empagliflozin had an association with decreased hospitalization for heart failure and other cardiovascular diseases. A strong recommendation for using empagliflozin depending on the available data. The effects of empagliflozin on hospitalization for heart failure or unstable angina require more examination in the future.37 0