The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia-Reperfusion.

Giovanna Casili,Emanuela Esposito,Rossella Basilotta,Alessia Filippone,Alessio Ardizzone,Michela Campolo,Irene Paterniti,Marika Lanza

doi:10.3390/ijms222111886

Giovanna Casili, Emanuela Esposito + Show 6 more

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https://doi.org/10.3390/ijms222111886

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Abstract

Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by blood circulation disorder caused by various factors, such as traumatic shock, surgery, organ transplantation, and thrombus. Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. The kidney is a highly perfused organ, sensitive to ischemia and reperfusion injury, and the incidence of renal IRI has high morbidity and mortality. Several studies showed that infiltration of inflammatory cells, apoptosis, and angiogenesis are important mechanisms involved in renal IRI. Despite advances in research, effective therapies for renal IRI are lacking. Recently it has been demonstrated the role of KYP2047, a selective inhibitor of prolyl oligopeptidase (POP), in the regulation of inflammation, apoptosis, and angiogenesis. Thus, this research focused on the role of POP in kidney ischemia/reperfusion (KI/R). An in vivo model of KI/R was performed and mice were subjected to KYP2047 treatment (intraperitoneal, 0.5, 1 and 5 mg/kg). Histological analysis, Masson’s trichrome and periodic acid shift (PAS) staining, immunohistochemical and Western blots analysis, real-time PCR (RT-PCR) and ELISA were performed on kidney samples. Moreover, serum creatinine and blood urea nitrogen (BUN) were quantified. POP-inhibition by KYP2047 treatment, only at the doses of 1 and 5 mg/kg, significantly reduced renal injury and collagen amount, regulated inflammation through canonical and non-canonical NF-κB pathway, and restored renal function. Moreover, KYP2047 modulated angiogenesis markers, such as TGF-β and VEGF, also slowing down apoptosis. Interestingly, treatment with KYP2047 modulated PP2A activity. Thus, these findings clarified the role of POP inhibition in AKI, also offering novel therapeutic target for renal injury after KI/R.

Highlights

Acute kidney injury (AKI) is a major medical problem [1], associated with high morbidity, mortality, and increased costs of treatment in both adult and pediatric population [2].Renal ischemia/reperfusion (I/R) injury is a common cause of AKI; this injury initiates complex events within the kidney in renal injury and death of renal cells [3]
Ischemia/reperfusion injury (IRI) contributes to pathological conditions, called acute kidney injury (AKI), which is a clinical syndrome with rapid kidney dysfunction and high mortality rates [6]
AKI represents a clinical syndrome with rapid renal dysfunction, histologically is characterized by major reductions in glomerular filtration rate, extensive tubular damage, tubular cell necrosis, glomerular injury, and signs of tubular obstruction with cell debris [17,18]

Summary

Introduction

Acute kidney injury (AKI) is a major medical problem [1], associated with high morbidity, mortality, and increased costs of treatment in both adult and pediatric population [2]. Renal ischemia/reperfusion (I/R) injury is a common cause of AKI; this injury initiates complex events within the kidney in renal injury and death of renal cells [3]. Novel therapeutic solutions need to be explored to improve the outcomes of AKI. IRI contributes to pathological conditions, called acute kidney injury (AKI), which is a clinical syndrome with rapid kidney dysfunction and high mortality rates [6]. The pathophysiology of KI/R is very complex, but some pathological pathways, such as activation inflammatory mediators, release of neutrophils, apoptosis, and angiogenesis are involved

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