Abstract
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) leading to renal fibrosis. Here, we investigate the kinetics of autophagy, apoptosis, and necroptosis activation in tubular epithelial cells (TECs) and peritubular capillaries (PTCs) after renal IRI, and their relative contributions to renal fibrogenesis. IRI with renal artery clamping in GFP-LC3 transgenic mice induced a predominant and sustained necroptotic response in TECs, while apoptosis and autophagy played minor roles. PTCs showed early and persistent activation of apoptosis, brief necroptosis induction, and increased autophagy at a distance from IRI. Disruption of the autophagic process with chloroquine (CHQ) injections in association with renal IRI did not modulate tubular death but enhanced PTC apoptosis and increased microvascular rarefaction and fibrosis. Apoptosis-deficient GFP-LC3/Caspase-3–/– mice exposed to renal IRI showed enhanced PTC autophagy, reduced PTC rarefaction, and inhibition of renal fibrosis, in spite of increased necroptosis in TECs. Inhibition of both autophagy with CHQ and apoptosis in GFP-LC3/Caspase-3–/– mice led to a marked switch toward necroptosis in PTCs. This was associated with aggravated microvascular rarefaction, increased leukocyte infiltration, and enhanced renal fibrosis. These findings establish a predominant role for PTC autophagy and caspase-3–dependent apoptosis in the development of renal fibrosis after IRI.
Authors
Hyunyun Kim, Francis Migneault, Shanshan Lan, Imane Kaci, Julie Turgeon, Annie Karakeussian Rimbaud, Martin Dupont, Shijie Qi, Mélanie Dieudé, Marie-Josée Hébert
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