PhD Scientific Days 2022

Budapest, 6-7 July 2022

Molecular Sciences II.

Perinatal asphyxia induced acute and long-term renal damage in a rat model

Lakat T.1,2; Hosszu A.1,2; Toth AR.1,2; Molnar A.2; Demeter K.3; Varga ZK.6; Kelemen H.2,3; Szabo AJ.2,4; Denes A.5; Szabo M.2; Mikics E.6; Fekete A.1,2

1MTA-SE „Lendület” Diabetes Research Group, Budapest, Hungary
2SE 1st Department of Pediatrics, MTA Centre of Excellence, Budapest, Hungary
3Behavioral Studies Unit, Institute of Experimental Medicine, Budapest, Hungary
4ELKH-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
5Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary
6Laboratory of Translational Behavioural Neuroscience, Institute of Experimental Medicine, Budapest, Hungary

Text of the abstract

Introduction
Perinatal asphyxia (PA) leads to the death of more than 800 000 mature newborns yearly. It is associated with serious multi-organ complications, however, the pathomechanism is not clarified yet, therapies and biomarkers are lacking.

Aims
Our aims were to determine the acute and long-term renal impairment following mild PA and to identify pathways and underlying correlations involved in the pathomechanism. We also aimed to investigate permanent renal susceptibility to ischemia/reperfusion (IR) injury in adulthood.

Method
7 day-old male Wistar rats were randomly grouped and placed in (i) Control (15 min; normal air) or (ii) PA (15 min; 4% O2; 20% CO2 in N2) chambers. Serum and kidney samples were collected after 4h, 24h and 6 months. In a second experiment 35 min bilateral renal IR was performed on Control and PA rats aged 6 months. Serum and kidney samples were collected 24 hours after reperfusion. Serum levels of kidney function parameters were determined. Expressions of tubular injury markers (KIM-1, NGAL), hypoxic (HIF-1α), inflammatory (IL-1α/-1β/-6, TNF-α), pro-fibrotic genes (TGF-ß, PDGF, CTGF) and heat shock proteins (HSF-1, HSP-27/-72) were investigated. Periodic-Acid Schiff staining and anti-CD68 labeling were performed on kidney sections. Random Forest analysis (RF) was performed on selected parameters.

Results
Blood urea nitrogen (BUN) remained elevated throughout life following PA. Expression of tubular injury and heat shock markers increased, hypoxic, inflammatory and pro-fibrotic pathways were activated in the kidney shortly after PA. RF revealed a trinomial model with a diagnostic accuracy of 95.5%. Mild PA caused no histological changes. Adult PA rats were more susceptible to renal IR, confirmed by higher serum creatinine and BUN levels, as well as increased expression of tubular injury, hypoxic and inflammatory markers compared to Controls.

Conclusion
Subclinical renal impairment was observed after mild PA. Parameters identified by RF may be potential candidates of further PA biomarker research. PA may increase sensitivity to renal IR even in adulthood, which may be worth considering in clinical situations with potential renal impairment such as major surgeries.

Funding
OTKA (PD131637, K135398), LP2021-3/2021, PC2022-8/2022, TKP2021-EGA-24, KDP-2020/1019145, Supported by the ÚNKP-21-3-II-SE-58 New National Excellence Program