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Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control

Abstract

Altogether, the three subprojects that integrate this proposal aim to elucidate novel molecular mechanisms underlying the renal tubular actions of antidiabetic drugs and their pharmacological targets. The first subproject intends to explore the molecular basis of the renal tubular effects of gliflozins. More specifically, we will investigate the mechanisms by which the pharmacological and/or genetic inhibition of the Na+/glucose cotransporter (SGLT2) reduces the activity of the Na+/H+ exchanger isoform 3 (NHE3) in the proximal tubule. Additionally, we will test the hypothesis that gliflozins attenuate cisplatin-induced hypomagnesemia through the upregulation of membrane transporters and/or ion channels that mediate renal magnesium reabsorption. Furthermore, we will investigate whether the renal tubular actions of gliflozins may be mediated by targets other than SGLT2 and isolate, identify and validate these potential targets. In the second subproject, we intend to test the hypothesis that endogenous GLP-1 protects against salt-sensitive hypertension. We will also verify whether there is an association between impaired bioavailability of this incretin hormone and blood pressure levels and markers of activation of intrarenal neurohumoral systems in experimental models of arterial hypertension and hypertensive patients. In the third subproject, we propose to unravel the physiological and pathophysiological role of the enzyme dipeptidyl peptidase 4 (DPP4) in the renal proximal tubule. Studies will be conducted to understand the interplay between DPP4, NHE3, and angiotensin II under physiological conditions and the role of these interactions in the pathophysiology of arterial hypertension, considering the influence of sexual dimorphism. Additionally, proteomic and phosphoproteomic experiments will be carried out to identify differentially expressed and differentially phosphorylated proteins in the kidney of mice with specific deletion of DPP4 in the renal proximal tubule. The results obtained from this project may provide a better understanding of the role of the kidneys in the maintenance of volume, blood pressure, and glycemic homeostasis and how disturbances in renal tubular function can contribute to the pathophysiology of cardiovascular diseases. Furthermore, our findings may enable the development of new therapeutic strategies and provide a scientific basis for better pharmacological management of patients with cardiovascular, renal, and metabolic diseases. (AU)

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