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    1. 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.

  2. Jan 2025
    1. for - Youtube -Right way to eat sugar - No inflammation - health - diet - how to minimize insulin spike when eating sugar - Dr. Anshul Gupta M.D. 2024 Nov

      summary - combine with protein or good faats to slow down sugar release - exercise 15 minutes after eating sugar - eat in the morning, not the evening - eat small portions - stevia and monkfruit are the only sugar substitutes

  3. Jul 2024
  4. Jan 2024
    1. for - healthy eating - Dr. William Li - nutrition - healthy food - inflammation - angiogenesis

      summary - A good interview about human health and healthy diet. William Li begins by talking about angiogenesis as a key aspect of human health - and how pathology of angiogenesis is at the root of many major diseases. - The interviewer then asks Dr. Li about the connection between another keystone disease, and angiogenesis. - Dr. Li then describes some healthy foods and good dietary practices including extra virgin olive oil.

      adjacency - between - angiogenesis - inflammation - Micheal Levine's work - evolutionary biology - adjacency statement - they all seem related, as evolutionary biology has created legacy subsystems within the human body

    2. if a tumor is kind of like a wound it can hijack blood vessels and you got inflammation and now the cancer itself causes some inflammation you're just making it a hell of a lot 00:28:49 easier for that tumor to get a blood supply which means that the cancer is more likely to grow

      for - adjacency - cancer - inflammation - angiogenesis

      adjacency - between - cancer - angiogenesis - inflammation - adjacency statement - if a tumor is kind of like a wound - it can hijack blood vessels - if you have some form of chronic inflammation - and cancer causes inflammation - it makes it easier to access blood supply - making cancer growth more likely

    3. diseases with chronic inflammation 00:28:24 like lupus like rheumatoid arthritis like diabetes

      for - diseases with chronic inflammation - lupus - rheumatoid arthritis - diabetes

    4. inflammation sends the signals for wound healing for healing that for blood vessels to grow

      for - example - relationship between inflammation and angiogenesis

      example - relationship between inflammation and angiogenesis - when you cut your finger and start bleeding, your wound will swell up - that's inflammation, your bodies immune system russhing in to fight bad bacteria - after a day or so, inflammation stops and it sends a signal to your body to begin creating new blood vessels - angiogenesis begins. - after awhile that stops as well and your body returns to the normal setpoint

    5. let's take a look at just sort of something everybody recognizes and to show how inflammation and blood vessel growth are go hand in hand

      for - relationship - inflammation and angiogenesis

    6. can you speak a little bit about the relationship between inflammation and angiogenesis

      for - question - angiogenesis and inflammation

  5. Nov 2023
    1. for those people who have sleep apnea try gargling with salt water before you 00:14:31 go to bed you may be amazed 40 50 percent of you may say the next morning i don't know what the heck happened but guess what salt water 00:14:42 reduces inflammation so gargling with salt water can be a cure for many of those conditions
      • for: sleep apnea - potential treatment - gargling salt water to reduce inflammation, sleep apnea - potential treatment - eliminate sugar
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  12. Aug 2020
    1. Luban, J., Sattler, R., Mühlberger, E., Graci, J. D., Cao, L., Weetall, M., Trotta, C., Colacino, J. M., Bavari, S., Strambio-De-Castillia, C., Suder, E. L., Wang, Y., Soloveva, V., Cintron-Lue, K., Naryshkin, N. A., Pykett, M., Welch, E. M., O’Keefe, K., Kong, R., … Peltz, S. (2020). The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines. BioRxiv, 2020.08.05.238394. https://doi.org/10.1101/2020.08.05.238394

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  15. Jan 2019
    1. Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance.