Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation Potential Conflicts of Interest: None

PUNCHLINE Endothelial ANGPTL4 drives diabetic kidney fibrosis by disrupting cellular metabolism, triggering inflammation, and damaging the vasculature.

BACKGROUND Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide, affecting millions and placing a growing burden on healthcare systems. While the disease is characterized by progressive scarring and vascular damage in the kidneys, the root causes remain incompletely understood. Emerging evidence suggests that subtle shifts in how kidney endothelial cells generate and use energy may play a central role in disease progression. The renal vasculature does more than transport blood; it regulates communication with surrounding cells and helps maintain metabolic balance. In diabetes, this balance is disrupted, leading to endothelial dysfunction, inflammation, and fibrotic remodeling. ANGPTL4, a protein involved in lipid metabolism and vascular homeostasis, has been implicated in kidney injury, but its specific role in the endothelium has remained unclear. This study investigates whether targeting ANGPTL4 in endothelial cells can break the cycle of metabolic dysfunction and fibrotic signaling in diabetic kidneys.

KEY QUESTION ADDRESSED Can reprogramming the metabolism of endothelial cells by deleting ANGPTL4 interrupt the cascade of vascular dysfunction, inflammation, and fibrosis that drives diabetic kidney disease?

SUMMARY This study uses a mouse model of endothelial-specific ANGPTL4 deletion to demonstrate that ANGPTL4 is a key upstream mediator of diabetic kidney pathology. In diabetic settings, endothelial ANGPTL4 promotes glycolysis and de novo lipogenesis while suppressing fatty acid oxidation—triggering mitochondrial damage, cGAS-STING–mediated inflammation, and vascular leakage. These metabolic shifts contribute to fibrosis through endothelial-to-mesenchymal transition (EndMT) and paracrine signaling to tubular epithelial cells. Mice lacking ANGPTL4 in the endothelium are protected from albuminuria, glomerulosclerosis, and fibrotic remodeling. ANGPTL4-deficient endothelium also displays a favorable switch from VEGFR1 to VEGFR2 signaling, downregulation of DPP-4/β1-integrin pathways, and upregulation of the anti-inflammatory metabolic regulator SIRT1. These protective effects are recapitulated by pharmacological inhibition of lipogenesis, glycolysis, or STING signaling, supporting a broader therapeutic strategy targeting endothelial metabolism. While direct ANGPTL4 inhibitors are not yet clinically validated, modulators of FASN, STING, and SIRT1 are further along in development, suggesting nearer-term translational opportunities.

KEY RESULTS ANGPTL4 is upregulated in diabetic kidney endothelium and correlates with increased vascular permeability, glycolysis, EndMT, and mitochondrial dysfunction (Fig. 1).

Endothelial-specific ANGPTL4 knockout mice (Angptl4^emut^) show protection from DKD, with reduced fibrosis, glomerular damage, and albuminuria despite persistent hyperglycemia (Fig. 2).

ANGPTL4 loss reprograms endothelial metabolism, enhancing fatty acid oxidation and suppressing glycolysis and lipogenesis (Figs. 2–3).

ANGPTL4-deficient endothelium avoids mitochondrial DNA release, blunting cGAS-STING activation and cytokine-driven inflammation (Fig. 4).

Pharmacologic inhibition of STING or FASN reproduces the protective effects, supporting a causal role for metabolic-immune crosstalk (Figs. 3–4).

ANGPTL4 deletion shifts VEGF signaling (VEGFR1→VEGFR2) and blocks downstream mesenchymal signaling to tubules via DPP-4/β1-integrin (Fig. 5).

SIRT1 expression is upregulated in ANGPTL4-deficient endothelium, potentially linking metabolic rewiring to anti-fibrotic resilience (Supp. Figs. S11–S12).

STRENGTHS Utilizes cell-type–specific genetic tools to dissect endothelial contributions in a robust diabetic kidney model.

Provides mechanistic insight into how metabolic alterations drive inflammation and fibrosis.

Combines in vivo models with molecular assays, metabolic flux analyses, and histopathology.

Demonstrates therapeutic relevance through complementary pharmacologic interventions.

Supports a conceptual shift in DKD from a purely metabolic or hemodynamic condition to a vascular-metabolic disorder.

FUTURE WORK & EXPERIMENTAL DIRECTIONS Elucidate how ANGPTL4 regulates SIRT1 expression and activity in endothelial cells.

Investigate ANGPTL4’s role in fibrotic progression across other diseases, such as aging-related or hypertensive kidney injury.

Explore sex-specific responses and long-term outcomes in ANGPTL4-deficient models.

Evaluate the therapeutic efficacy of ANGPTL4 inhibition or SIRT1 activation in vascularized human kidney organoids or ex vivo human kidney tissues with preserved endothelial architecture.

Examine interactions between endothelial cells, podocytes, and immune cells in diabetic nephropathy.

RELEVANCE TO RECENT LITERATURE This work builds on the authors’ prior study in Science Advances (2024), which showed that podocyte- and tubule-derived Angptl4 is fibrogenic in diabetic kidneys. It strengthens the case that DKD is not simply a byproduct of hyperglycemia but an actively regulated process involving endothelial metabolic stress, immune signaling, and fibrogenesis. Similar to prior reports on glycolysis suppression and SIRT1 enhancement as anti-fibrotic strategies, this study identifies ANGPTL4 as a critical mediator linking lipid metabolism, mitochondrial damage, and endothelial inflammation. It underscores a growing consensus that endothelial metabolism governs kidney health and positions ANGPTL4 as a novel, actionable target for therapeutic intervention in DKD.

AUTHORSHIP NOTE This review was drafted with the assistance of ChatGPT (OpenAI) to organize and articulate key insights. Dr. Angela Andersen reviewed the final content for accuracy and clarity.

FINAL TAKEAWAY This preprint reframes diabetic kidney disease as a vascular-metabolic disorder driven by ANGPTL4-mediated metabolic reprogramming in endothelial cells. By connecting mitochondrial dysfunction, immune activation, and fibrotic signaling, it clarifies a central mechanism in DKD progression and highlights promising new therapeutic strategies targeting endothelial metabolism.

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IPW may reverse brain aging by inhibit TGFbeta