Angiopoietin-like-3 knockout protects against glomerulosclerosis in murine adriamycin-induced nephropathy by attenuating podocyte loss

Abstract

Background 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 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. Methods B6; 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. Results Angptl3 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. Conclusion In 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. Electronic supplementary material The online version of this article (10.1186/s12882-019-1383-1) contains supplementary material, which is available to authorized users.

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis

“…This is consistent with previous animal experiments in which the Angptl3 knockout was associated with improved renal structure and function and also a delayed disease progression. 17 It might thus be worth to assess the role of ANGPTL3 inhibitors in possible prevention and treatment of kidney diseases in forthcoming trials.…”

RNA Interference Targeting Liver Angiopoietin-Like Protein 3 Protects from Nephrotic Syndrome in a Rat Model Via Amelioration of Pathologic Hypertriglyceridemia

“…These observations have led to the intriguing possibility of utilizing Angptl3 targeting therapies to prevent dyslipidemia of NS and thus ameliorate symptoms of NS (Jiang et al, 2019;Mace and Chugh, 2014). In accordance with this idea, other investigators have shown that deletion or decreased expression of Angptl3 ameliorates proteinuria and protects renal structure and function in animal models of nephrotic syndrome (Dai et al, 2015;Dai et al, 2019;Liu et al, 2015). In addition, the feasibility of a siRNA mediated approach to mitigate NS is highly supported by other successful and safe siRNA treatments for dyslipidemia such as the PCSK9 inhibitor Inclisiran, developed using a similar siRNA technology (Fitzgerald et al, 2017;Ray et al, 2020) In the current study, we found that administration of a hepatocyte targeted Angptl3 specific siRNA formulation in rats with Puromycin-induced NS was associated with a significant decrease in serum TGs, but no change in serum cholesterol or LDL levels.…”

“…ANGPTL3 is a secreted protein which is mainly expressed in hepatocytes (Conklin et al, 1999). Recent studies have found that the Angptl3 knockdown via siRNA or use of knock out animal models markedly ameliorated these findings, improved structure and integrity of podocyte and decreased proteinuria (Dai et al, 2015;Dai et al, 2019;Lin et al, 2013;Liu et al, 2015). NS, in addition to heavy proteinuria and glomerular disease (as evidenced by heavy proteinuria, glomerulosclerosis) also results in tubulointerstitial disease marked by inflammation and oxidative stress.…”

Systemic gene therapy with thymosin β4 alleviates glomerular injury in mice

“…To induce glomerular damage in vivo , we administered ADR, a chemotherapeutic drug, to male BALB/c mice. In BALB/c mice ADR replicates some of the features of human focal segmental glomerulosclerosis (FSGS) 33 and has toxic effects on podocytes in vitro and in vivo , including cytoskeletal disorganisation, foot process effacement and a loss of podocyte viability 9,34,35 . Firstly, we examined if ADR administration altered glomerular TB4 expression.…”