Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors.

Abstract

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

• Authors: Milton Packer
• Journal: American journal of nephrology (Am J Nephrol) Vol. 51 Issue 4 Pg. 289-293 ( 2020) ISSN: 1421-9670 [Electronic] Switzerland
• PMID: 32126558 (Publication Type: Editorial)
• Copyright: © 2020 S. Karger AG, Basel.

Chemical References

• Adipokines
• Sodium-Glucose Transporter 2 Inhibitors
• AMP-Activated Protein Kinases
• SIRT1 protein, human
• Sirtuin 1

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adipokines (metabolism)
• Adipose Tissue (drug effects, immunology, metabolism)
• Autophagy (drug effects)
• Diabetes Mellitus, Type 2 (complications, drug therapy, metabolism)
• Diabetic Nephropathies (etiology, metabolism, prevention & control)
• Endoplasmic Reticulum Stress (drug effects)
• Energy Metabolism (drug effects)
• Glomerular Filtration Rate (drug effects)
• Humans
• Kidney (drug effects, metabolism, physiopathology)
• Lipid Metabolism (drug effects)
• Lysosomes (drug effects, metabolism)
• Nutrients (metabolism)
• Obesity (complications, drug therapy, metabolism)
• Oxidative Stress (drug effects)
• Renal Insufficiency, Chronic (etiology, prevention & control)
• Signal Transduction (drug effects, immunology)
• Sirtuin 1 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)