RELEVANCE OF Hsp70 PHARMACOLOGICAL INHIBITION IN RENAL ISCHEMIA-REPERFUSION INJUR

RODRIGO DAMIÁN GARCÍA , TATIANA SILVINA FIGUERAS , VALERIA CACCIAMANI, ANDREA GIL LORENZO, EUGENIA BENARDON, PATRICIA G. VALLÉS, VALERIA VICTORIA COSTANTINO

MEDICINA (BUENOS AIRES)

MEDICINA (BUENOS AIRES)

Lugar: Buenos Aires; Año: 2022 vol. 82 p. 1 - 338

0025-7680

Acute kidney injury (AKI) as a consequence of ischemia-reperfusion injury (IRI) is a common clinical event that leads to high morbidity, mortality and chronic kidney disease. IRI is also an unavoidable consequence of kidney transplantation. IRI leads to inflammation and cellular injury as a result of activation of innate immunity. TLR4 (Toll-like Receptor 4) is a transmembrane receptor constitutively expressed in epithelial cells of proximal tubules. TLR4 mediates pro-inflammatory and pro-fibrotic pathways. Increased receptor activity on ischemic epithelial cells after IRI leads to apoptotic cell death, inflammation and fibrosis. AKI induces an increase of stress-activated chaperones expression such as Hsp70 (heat shock protein 70). The Hsp70 protective properties in renal IRI are not fully understood and putative modes of protection include anti-inflammatory and anti-apoptotic effects. We propose to evaluate the Hsp70 pharmacological inhibition effect in renal IRI. For this, C57 BL6 wild type (WT) and TLR4 knockout (KO) mice were injected with KNK 437 (Hsp70 expression inhibitor) 48 h before IRI. Uni and bilateral IRI was performed by clamping the renal pedicles for 30 min. Controls underwent the same surgical procedure, but the renal pedicle was not clamped. Mice were sacrificed 1, 2, and 7 days after IRI. Blood samples were collected by cardiac puncture and then nephrectomized to obtain tissue samples. Survival curves at 7 days post-IRI showed that KO mice have higher survival percentage and lower serum creatinine and urea concentrations compared to WT mice. However, in WT and KO mice pretreated with KNK 437 the survival percentage significantly decreased compared to untreated mice. This was accompanied by a significant increase in urea concentration. These results suggest that TLR4 KO mice present improvement in renal IRI, while Hsp70 inhibition impairs it, suggesting a protective role of Hsp70 in IRI possibly by modulating TLR4-mediated cellular responses.