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Targeting ANGPTL3 and IL-33/ST2 Ameliorates Diabetic Kidney Disease by Reducing Lipotoxicity, Alleviating
Zhuojin Li1,2, Zhonglian Cao1, Rongrui Zhou1
1School of Pharmaceutical Sciences and Shanghai Engineering Research Center of Immunotherapeutics, Qidong-Fudan Innovative Institute of Medical Sciences, Fudan University, Shanghai, China.
Abstract:
Current therapies for diabetic kidney disease (DKD) targeting hyperglycemia and hypertension fail to halt progression, urging exploration of additional drivers. Renal lipotoxicity and chronic inflammation form a self-perpetuating cycle driving DKD, yet multitarget interventions remain underexplored. We hypothesized that simultaneous inhibition of ANGPTL3 and IL-33, two key regulators of lipid metabolism and the inflammatory-fibrotic axis, would ameliorate DKD, and that integrating both antagonistic activities into a single bifunctional molecule offers translational advantages. We engineered a bifunctional fusion protein, FD03-sST2, comprising an anti-ANGPTL3 nanobody fused to the IL-33 decoy receptor sST2. In high-fat diet-fed db/db mice, FD03-sST2 significantly improved renal function (ACR, BUN, urine volume), reduced serum/hepatic lipids, and attenuated renal lipid accumulation. Mechanistically, it suppressed renal inflammation via NF-κB/NLRP3 inhibition and ameliorated fibrosis by suppressing the IL-33/ST2/ILC2 axis (reducing renal IL-33/GATA3 signals and inhibiting IL-33-induced profibrotic factors from ILC2s). Transcriptomic and metabolomic analyses confirmed attenuation of DKD-associated dysregulation. This study identifies a DKD cascade wherein lipotoxicity triggers IL-33 release, amplifying injury through inflammation and fibrosis. By targeting ANGPTL3 and IL-33 simultaneously, FD03-sST2 interrupts this vicious cycle at two nodes-improving lipid metabolism while suppressing downstream inflammatory and fibrotic signaling-providing an integrated alternative to separate biologics.
Insights
A novel bifunctional fusion protein, FD03-sST2, simultaneously targets ANGPTL3 and IL-33 to combat diabetic kidney disease (DKD). This approach improves lipid metabolism and reduces inflammation and fibrosis, offering a new therapeutic strategy for DKD.
Area of Science:
- Nephrology
- Metabolic Diseases
- Immunology
Background:
- Current diabetic kidney disease (DKD) therapies targeting hyperglycemia and hypertension are insufficient to halt disease progression.
- Renal lipotoxicity and chronic inflammation create a cycle that drives DKD, but multitarget interventions are underexplored.
Purpose of the Study:
- To investigate the simultaneous inhibition of ANGPTL3 and IL-33 for DKD amelioration.
- To engineer a single bifunctional molecule, FD03-sST2, integrating anti-ANGPTL3 and IL-33 decoy activities for translational advantages.
Main Methods:
- Engineered a bifunctional fusion protein (FD03-sST2) combining an anti-ANGPTL3 nanobody with the IL-33 decoy receptor sST2.
- Administered FD03-sST2 to high-fat diet-fed db/db mice.
- Assessed renal function, serum/hepatic lipids, renal lipid accumulation, inflammation, fibrosis, and performed transcriptomic/metabolomic analyses.
Main Results:
- FD03-sST2 significantly improved renal function (reduced ACR, BUN) and urine volume in mice.
- Reduced serum and hepatic lipids, and attenuated renal lipid accumulation.
- Suppressed renal inflammation (NF-κB/NLRP3 inhibition) and fibrosis (IL-33/ST2/ILC2 axis suppression), confirmed by transcriptomic and metabolomic data.
Conclusions:
- Identified a DKD cascade where lipotoxicity triggers IL-33 release, amplifying injury via inflammation and fibrosis.
- FD03-sST2 effectively interrupts this cycle by targeting both ANGPTL3 and IL-33, improving lipid metabolism and suppressing inflammatory/fibrotic signaling.
- This bifunctional approach offers an integrated alternative to separate biologics for DKD treatment.
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