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Abstract: TH-PO010

Mineralocorticoid Receptor Antagonism Counteracts the Acute and Chronic Effects of Renal Ischemic Injury in Rodents and the Large White Pig

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Jaisser, Frederic, INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
  • Estrela, Gabriel R., INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
  • Giraud, Sebastien, INSERM U1082- CHU de Poitiers, service de biochimie, Poitiers, France
  • Kaaki, Sihem, INSERM U1082- CHU de Poitiers, service de biochimie, Poitiers, France
  • Hauet, Thierry, INSERM U1082- CHU de Poitiers, service de biochimie, Poitiers, France
  • Kolkhof, Peter, BAYER AG, Wuppertal, Germany
  • Barrera-Chimal, Jonatan, Instituto de Investigaciones Biomédicas, UNAM and Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico
Background

Mineralocorticoid receptor antagonists (MRA) prevent ischemic acute kidney injury (AKI) and its transition to chronic kidney disease (CKD) through macrophage polarization modulation. The specific contribution of interleukin-4 (IL-4) signaling to this effect is unknown. Whether the MRA protective effect reported in rodents can be translated to the human remains to be elucidated. Here, we explore the role of IL-4 signaling in the protective effect of Finerenone and we evaluate the effect of MRA against the acute and chronic effects of ischemic AKI in the Large White pig.

Methods

Male C57/B6 mice (24) were divided in: sham, renal ischemia for 22.5 min (IR), IR plus the non-steroidal MRA finerenone (10 mg/kg) at -48, -24 and -1 h before IR and IR-finerenone plus Tofacitinib (15mg/kg), a JAK3 inhibitor. The mice were followed-up for 4 weeks to evaluate the AKi to CKD transition. Large White male pigs (18) were divided in: sham, bilateral renal ischemia for 60 min + vehicle and IR + Soludactone (potassium canreonate-7mg/kg, i.v.) at 48 h, 24 h and 30 min before the induction of the ischemia and 24 h and 48 h after reperfusion.

Results

In mice, the AKI to CKD transition was evidenced by a 40% increase in plasma creatinine, interstitial fibrosis and increased mRNA levels of α-SMA, fibronectin and collagen I. Finerenone protected against these alterations while the JAK3 inhibitor partially reversed this protective effect. In the Large White pig, tubular injury protection by canrenoate was evidenced by a significant reduction in urinary protein (Vehicle: 1±0.08 g/mmol vs canrenoate: 0.49±0.02 g/mmol), L-FABP (Vehicle: 39±2 ng/mL vs canrenoate: 19±.1.5 ng/mL), NAG excretion (Vehicle: 109±3 U/L vs canrenoate: 59±2 U/L) and by the recovery of the urinary concentration capacity after 24 h of renal ischemia. After 3 months, the untreated pigs presented proteinuria (0.03±0.01 g/mmol) which was absent in the canreonate-treated pigs (0.01±0.01 g/mmol).

Conclusion

MR antagonism prevents the acute and chronic IR-kidney effects in the mice and in the Large White pig. The IL-4 receptor-JAK3 signaling pathway is involved in the benefit of the MRA finerenone. These findings support clinical trials testing the potential benefits of MRAs in the kidney transplantation setting.

Funding

  • Commercial Support –