PhD Scientific Days 2019

Budapest, April 25–26, 2019

SGLT2 inhibitors are renoprotective via minimizing tubular hypoxia and protein O-GlcNAcylation

Balogh, Dóra Bianka

Dora B. Balogh1,4, Judit Hodrea1,4, Lilla Lenart1,4, Adam Hosszu1,4, Csenge Mezei1,4, Tamas Lakat1,4, Agnes Molnar1,4, Laszlo J. Wagner3, Attila J. Szabo2,4, Andrea Fekete1,4

1. MTA-SE „Lendület” Diabetes Research Group, Budapest
2. MTA-SE Pediatrics and Nephrology Research Group, Budapest
3. Department of Transplantation and Surgery, Semmelweis University, Budapest
4. 1st Department of Pediatrics, Semmelweis University Budapest

Language of the presentation

English

Text of the abstract

Introduction: Identification of novel therapeutic strategies that reduce the risk of diabetic kidney disease (DKD) is a research priority. Tubular hypoxia has a major pathogenic role in DKD. Hypoxia is in strong association with elevated glucose reabsorption and increased protein O-GlcNAcylation which could contribute to renal fibrosis. We recently described that SGLT2 inhibitors (SGLT2i) are renoprotective in experimental type 1 diabetes.

Aims: Considering emerging evidence of proximal tubular involvement in DKD and the major role of SGLT2 in glucose metabolism, here we investigated the direct effects of SGLT2i on hypoxia and O-GlcNAcylation.

Methods: Renal function and fibrosis were evaluated. The effect of hyperglycaemia was tested in human proximal tubular epithelial cells (HK-2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions for 24 hours. HG cells were treated with 10 µM DAPA. O-GlcNAc, O‑GlcNAc transferase (OGT) and O‑GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 µM DAPA and were placed in a hypoxic chamber for 2 hours (1% O2, 5% CO2, 94% N2). HIF-1α, EPO, VEGFA and PAI-1 were measured. Immunocytochemistry (ICC) staining for HIF-1α was performed.

Results: DAPA minimized hyperglycemia-induced total protein O-GlcNAcylation and OGT, while OGA which removes O-GlcNAc moieties was elevated in HK-2 cells. Hypoxia-induced HIF-1α elevation was suspended by DAPA treatment. Abolishment of HIF-1α upregulation by DAPA was confirmed by ICC staining. EPO, VEGFA and PAI-1 levels were also increased in hypoxia and DAPA prevented EPO and PAI-1 elevation.

Conclusions: Here we identified a novel mechanism of SGLT2i by which the direct reduction of tubular hypoxia and inhibition of OGT by DAPA results in decreased O-GlcNAcylation in proximal tubular cells. These processes could contribute to improved renal function and alleviated kidney fibrosis.

Funding: LP008/2017, OTKA-K112629-FK124491-NN-114607, VKE-2017-00006, FIKP, ÚNKP-18-3

Data of the presenter

Doctoral School: Clinical Medicine
Program: Prevention of Chronic Diseases in Childhood
Supervisor: Andrea Fekete, MD Phd
E-mail address: dorabiankabalogh@gmail.com