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| Author(s): |
Monique de Fatima Mello Santana
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2020-09-04 |
| Examining board members: |
Marisa Passarelli;
Maria Cristina de Oliveira Izar;
Ubiratan Fabres Machado
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| Advisor: | Marisa Passarelli |
| Abstract | |
Diabetes mellitus kidney disease (DKD) is associated with lipid derangements worsening kidney function and enhancing cardiovascular (CV) risk. The management of dyslipidemia, hypertension and other traditional risk factors does not completely prevent CV complications bringing up the participation of untraditional risk factors such as advanced glycation (AGE), carbamoylation and changes in HDL proteome and functionality. In the present investigation it was analyzed HDL composition, proteome, chemical modification by advanced glycation and carbamoylation and functionality in non-dialytic DKD subjects categorized according to glomerular filtration rate (GFR) and urinary albumin excretion rate (AER). DKD individuals were divided in GFR > 60 mL/min/1.73 m2 plus AER stages A1 (< 30 mg/g creatinine) and A2 (30 - 300 mg/g creatinine) (n=10) and GFR < 60 plus A3 (> 300 mg/g creatinine( (n=25) and control subjects matched by age with (GFR > 60; n=8). HDL was isolated from plasma by ultracentrifugation and biochemical analysis performed by enzymatic techniques; carboxymethyllysine and carbamoylation by ELISA. Total AGE and pentosidine were determined by fluorimetry. HDL was utilized to measure 14C-cholesterol removal from macrophages, the inhibition of LDL oxidation induced by cooper sulfate and the modulation of cytokines secretion by LPS-challenged macrophages. HDL from GFR < 60+A3 presented higher levels of total AGE, pentosidine and carbamoylation (1.2, 1.1 and 4.2 times, respectively) in comparison to controls. The amount of phospholipids and apoA-I was reduced in this group as compared to control. Targeted proteomic analyses quantified 29 proteins associated with HDL in all groups, although only 2 were more expressed in GFR < 60+A3 group in comparison to controls: apolipoprotein D (apoD) and apoA-IV. As compared to controls, the HDL-mediated cholesterol efflux from macrophages was 33% reduced in GFR < 60+A3 although HDL from this group inhibited 95% the secretion of IL-6 and TNF-alpha. The antioxidant role of HDL (lag time for LDL oxidation) was similar among groups. The increment in apoA-IV that presents many antiatherogenic actions seems to counteract the HDL chemical modification by advanced glycation and carbamoylation and its increment in apoD that occurs in well-established DKD according to the increase in AER and reduction in GFR (AU) | |
| FAPESP's process: | 17/18545-4 - HDL proteomics and functionality in diabetes mellitus chronic kidney disease: association with advanced glycation end products |
| Grantee: | Monique de Fatima Mello Santana |
| Support Opportunities: | Scholarships in Brazil - Master |