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Potential biomarker and therapeutic target of dipeptidyl peptidase IV in Chronic Kidney Disease

Grant number: 19/09860-9
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2019
Effective date (End): September 30, 2023
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Acaris Benetti dos Santos
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:16/22140-7 - Molecular bases of renal tubular function and dysfunction, AP.TEM

Abstract

It is estimated in Brazil that more than 2 million people have Chronic Kidney Disease (CKD) at different stages and approximately 100,000 patients are in renal replacement therapy. However, therapeutic strategies to control the progression of CKD are limited to the control of basal diseases and the use of drugs that block the renin-angiotensin system. Thus there is an avid need for new agents aimed to mitigate CKD progression. In this context, inhibitors of the enzyme dipeptidyl peptidase IV (IDPPIV), a relative recent class of drugs used in the treatment of Type 2 Diabetes Mellitus, have shown to be not only effective and safe, but also renoprotective, for use in patients with CKD. In fact, research shows that these agents have repoprotective and cardioprotective actions in patients and experimental models with CKD associated or not associated with hyperglycemia, as well as in congestive heart failure. In addition, studies from our research group have shown that there is a progressive increase in the urinary excretion of DPPIV in rats with CKD, an increase that temporarily accompanies the reduction of the glomerular filtration rate and the glomerular and proximal tubular proteinuria. In addition, proteomic analysis performed on urine of pigs submitted to acute renal injury (ischemia-reperfusion) also suggests that urinary DPPIV may be a biomarker of renal damage. In view of the above, we propose to investigate the possible association of DPPIV with the progression of renal and cardiovascular dysfunction in patients with CKD. In addition, we will perform a metabolomic approach in renal proximal tubule cells and in neonatal cardiomyocytes exposed to serum of rats submitted to 5/6 (Nx) nephrectomy treated or not with IDPPIV, aiming to identify the enzymatic and metabolic pathways that the cardiorenal effects of IDPPIV. (AU)