Characterization of microvascular stress and cell death responses triggered by renal ischemia-reperfusion injury and their roles in progressive fibrosis
Acute kidney injury (AKI) is a crucial clinical event, with increasing incidence and mortality. Among various pathogenesis of AKI, ischemia-reperfusion injury (IRI) is an important etiology, especially in the renal post-transplant scenario. The complex of programmed cell deaths (PCD) developed in IRI-induced AKI has been proven in a number of investigations. Renal tubular epithelial injury has been considered as the major contributor in AKI and multiple programmed tubular epithelial cell (TECs) deaths have been demonstrated in the literature. However, renal microvascular endothelial injury is attracting more attention as an important inducer of microvascular dysfunction and renal progressive fibrosis. Some investigators, including our team, have reported the development of renal endothelial apoptosis in the condition of ischemia. Apoptosis, a commonly known programmed cell death, has been elucidated in both renal TECs and microvascular endothelial cells (ECs) post-IRI and the activation of caspase-3 functions as the key effector of caspase-dependent apoptosis. To verify the importance of apoptosis in IRI- induced AKI, we applied the in vivo murine renal IRI model in wild-type and caspase-3 KO mice, with clamping the renal artery for 30 minutes (mild AKI model) or 60 minutes (severe AKI model). In regard to the mild AKI model, our result demonstrates that caspase-3 deficiency prevents ECs apoptotic death in all phases of AKI, attenuating microvascular rarefaction, collagen deposition, and renal fibrosis, while maintaining physical endothelial permeability in the long-term. Meanwhile, caspase-3 deletion aggravates tubular injury in the short-term by promoting TECs necroptosis but ameliorates long-term tubular injury through preserved peritubular capillaries (PTCs) function. Furthermore, caspase-3 deficiency also demonstrated a protective effect against renal microvascular rarefaction, progressive renal fibrosis, as well as enhanced endothelial permeability in the severe AKI model. Conclusively, our findings determine the crucial effect of microvascular endothelial apoptosis as an inducer of renal microvascular dysfunction, microvascular rarefaction, and progressive renal fibrosis in the pathophysiology of mild and severe AKI induced by IRI. Additionally, our results demonstrate the predominant importance of microvascular endothelial injury over tubular epithelial injury in predicting renal function loss at long-term post-IRI.
Apoptosis Fibrosis Endothelial permeability Microvascular rarefaction Necroptosis Ischemia-reperfusion injury Acute kidney injury