Abstract
BackgroundAngiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy. The current study re-evaluated the renoprotective effect of Angptl3 knockout in chronic ADR nephropathy and attempted to explore the mechanism underlying the effect associated with Angptl3 knockout in glomerulosclerosis.MethodsB6; 129S5 mice were injected with ADR to induce nephropathy. Kidney structure and serum and urine parameters were observed during long-term follow-up. Cultured primary mouse podocytes were exposed to ADR and analyzed for the expression of some relative proteins. Podocyte loss was analyzed in both in vivo and in vitro experiments.ResultsAngptl3 knockout attenuated proteinuria and hypoproteinemia, protected renal structure and function, and improved the survival of mice over the whole process of ADR nephropathy. Furthermore, Angptl3 knockout reduced the numbers of the detached and apoptotic cells in the renal tissue and alleviated podocyte loss in mice with ADR chronic nephropathy, thereby, delaying the glomerulosclerosis formation. Additional results in vitro showed that Angptl3 knockout attenuated ADR-induced primary podocyte loss, including podocyte detachment and apoptosis.ConclusionIn addition to serving a renoprotective role in the early stage of ADR nephropathy, Angptl3 knockout contributed to disease amelioration throughout the ADR nephropathy process. Angptl3 knockout effectively delayed glomerulosclerosis formation by attenuating podocyte loss through rescuing podocytes from detachment and apoptosis. Angptl3 antagonists or inhibitors might have therapeutic potential in the occurrence and progression of nephropathy.
Highlights
Angiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy
The current study proposes that Angptl3 antagonists or inhibitors are potential and attractive therapeutic candidates for podocyte injury and proteinuria in the occurrence and progression of nephropathy, which has not been proposed in other studies
We demonstrated that Angptl3 knockout attenuated podocyte loss in mice with end-stage ADR nephropathy, and we suggested that most of the lost cells were podocytes
Summary
Angiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy. Our previous work revealed increased Angptl expression in the glomeruli of children with nephrotic syndrome (including minimal change disease and glomerulosclerosis) and animal models of Adriamycin (ADR) nephropathy, and in ADR- or puromycin aminonucleoside (PAN)- treated cultured podocytes [12,13,14,15,16]. Our previous results showed that Angptl knockout was associated with renoprotection in the early stage of ADR nephropathy [19]. ADR nephropathy usually progresses to end stage kidney disease, which is phenotypically characterized by glomerulosclerosis [20]. We found that Angptl knockout ameliorates ADR nephropathy in the early stage and protects against its progression. The current study proposes that Angptl antagonists or inhibitors are potential and attractive therapeutic candidates for podocyte injury and proteinuria in the occurrence and progression of nephropathy, which has not been proposed in other studies
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