Introduction:
Acute kidney injury (AKI) can predispose to the development of chronic kidney disease (CKD). The kidney has remarkable capacity for regeneration after mild-to-moderate AKI, but severe AKI can lead to maladaptive repair and CKD, termed AKI-to-CKD transition. Kidney Injury Molecule-1 (KIM-1) is a transmembrane receptor expressed by injured proximal tubular epithelial cells that recognizes phosphatidylserine, an “eat me” signal that marks them for phagocytic clearance. The aim of this study was to determine the role of KIM-1 in AKI-to-CKD transition and the underlying mechanism.
Methods:
Wild type (KIM-1+/+), global KIM-1 knockout (KIM-1-/-), as well as proximal tubule-specific KIM-1 knockout C57BL/6 mice were subjected to mild-to-moderate (25 min of renal pedicle clamping) or severe (45 min of clamping) unilateral ischemia reperfusion injury (IRI). Kidneys were isolated after 3, 7, 28, and 42 days of reperfusion and used for histopathological assessment, RNA isolation and protein extraction. The expression of KIM-1, Deoxyribonuclease I (DNase I), as well as proinflammatory and profibrotic factors were assessed using RT-PCR, immunofluorescence staining and/or Western blot. RNA sequencing was performed using total RNA isolated from ipsilateral and contralateral kidneys from KIM-1+/+ and KIM-1-/- mice kidneys subjected to unilateral IRI. To study the therapeutic potential of DNase I after severe unilateral IRI, KIM-1+/+ and KIM-1-/- mice were given repeated doses of DNase I or vehicle-solution (NaCl 0.9%), before and after reperfusion.
Results:
Renal KIM-1 expression was upregulated in all mice after IRI but was quickly downregulated in mice subjected to moderate IRI and remained upregulated until 42 days in mice subjected to severe IRI. By day 28, the injured kidneys of KIM-1+/+ mice subjected to severe unilateral IRI, but not moderate unilateral IRI, became markedly shrunken and fibrotic. Both global and tissue-specific KIM-1 knockout mice were protected from renal fibrosis caused by severe injury. We observed significant upregulation of various pro-inflammatory and pro-fibrotic mediators at both 7 and 28 days after severe injury in KIM-1+/+ kidney compared to KIM-1-/- kidneys. RNA sequencing identified DNase I as the most downregulated transcript in the kidneys of KIM-1+/+ mice when compared to those of KIM-1-/- mice. DNase I protein expression was significantly downregulated in KIM-1+/+ kidneys compared to KIM-1-/- kidneys at all time points analysed, and negatively correlated with renal injury and fibrosis scores. Administration of recombinant DNase I to KIM-1+/+ reversed renal inflammation and development of fibrosis after severe IRI.
Conclusions:
Severe AKI leads to sustained upregulation of KIM-1 which drives AKI-to-CKD transition in a DNase-I-dependent manner.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.