Abstract
BackgroundLong-term outcomes after acute kidney injury (AKI) include incremental loss of function and progression towards chronic kidney disease (CKD); however, the pathogenesis of AKI to CKD remains largely unknown. Clusterin (CLU) is a chaperone-like protein that reduces ischemia-reperfusion injury (IRI) and enhances tissue repair after IRI in the kidney. This study investigated the role of CLU in the transition of IRI to renal fibrosis.MethodsIRI was induced in the left kidneys of wild type (WT) C57BL/6J (B6) versus CLU knockout (KO) B6 mice by clamping the renal pedicles for 28 min at the body temperature of 32 °C. Tissue damage was examined by histology, infiltrate phenotypes by flow cytometry analysis, and fibrosis-related gene expression by PCR array.ResultsReduction of kidney weight was induced by IRI, but was not affected by CLU KO. Both WT and KO kidneys had similar function with minimal cellular infiltration and fibrosis at day 14 of reperfusion. After 30 days, KO kidneys had greater loss in function than WT, indicated by the higher levels of both serum creatinine and BUN in KO mice, and exhibited more cellular infiltration (CD8 cells and macrophages), more tubular damage and more severe tissue fibrosis (glomerulopathy, interstitial fibrosis and vascular fibrosis). PCR array showed the association of CLU deficiency with up-regulation of CCL12, Col3a1, MMP9 and TIMP1 and down-regulation of EGF in these kidneys.ConclusionOur data suggest that CLU deficiency worsens renal inflammation and tissue fibrosis after IRI in the kidney, which may be mediated through multiple pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0348-x) contains supplementary material, which is available to authorized users.
Highlights
Long-term outcomes after acute kidney injury (AKI) include incremental loss of function and progression towards chronic kidney disease (CKD); the pathogenesis of AKI to CKD remains largely unknown
We and others have been investigating the biological impacts of CLU deficiency on adult kidneys using CLU knockout (KO) mice compared to CLU-expressing wild type (WT) control mice, and have demonstrated: (i) CLU KO in aging mice results in developing progressive glomerulopathy that is associated with glomerular antibody deposition [30]; (ii) CLU KO mice exhibit the higher levels of renal fibrosis in response to ureteral obstruction [31] or angiotensin II stimulation [32]; and (iii) our group has shown that CLU KO results in more severe renal ischemia-reperfusion injury (IRI) [26], in an experimental model of ischemic AKI, and impairs renal repair after IRI [33]
Significant reduction of kidney weight is induced by IRI, but not affected by CLU deficiency It has been demonstrated that IRI initiates progressive renal atrophy, indicated by the reduction in renal weight, volume and cortical thickness accompanying tubular cell death and interstitial infiltration [37,38,39]
Summary
Long-term outcomes after acute kidney injury (AKI) include incremental loss of function and progression towards chronic kidney disease (CKD); the pathogenesis of AKI to CKD remains largely unknown. We and others have been investigating the biological impacts of CLU deficiency on adult kidneys using CLU knockout (KO) mice compared to CLU-expressing wild type (WT) control mice, and have demonstrated: (i) CLU KO in aging mice results in developing progressive glomerulopathy that is associated with glomerular antibody deposition [30]; (ii) CLU KO mice exhibit the higher levels of renal fibrosis in response to ureteral obstruction [31] or angiotensin II stimulation [32]; and (iii) our group has shown that CLU KO results in more severe renal IRI [26], in an experimental model of ischemic AKI, and impairs renal repair after IRI [33]. The effects of CLU deficiency on the transition of ischemic AKI to CKD were investigated using CLU KO mice in a model of renal IRI compared to WT controls
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