Molecular pathways that drive diabetic kidney disease
Samer Mohandes, … , Poonam Dhillon, Katalin Susztak
Samer Mohandes, … , Poonam Dhillon, Katalin Susztak
Published February 15, 2023
Citation Information: J Clin Invest. 2023;133(4):e165654. https://doi.org/10.1172/JCI165654.
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Molecular pathways that drive diabetic kidney disease

Abstract

Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney disease (DKD) is responsible for close to half of all chronic kidney disease cases. DKD usually develops in a genetically susceptible individual as a result of poor metabolic (glycemic) control. Molecular and genetic studies indicate the key role of podocytes and endothelial cells in driving albuminuria and early kidney disease in diabetes. Proximal tubule changes show a strong association with the glomerular filtration rate. Hyperglycemia represents a key cellular stress in the kidney by altering cellular metabolism in endothelial cells and podocytes and by imposing an excess workload requiring energy and oxygen for proximal tubule cells. Changes in metabolism induce early adaptive cellular hypertrophy and reorganization of the actin cytoskeleton. Later, mitochondrial defects contribute to increased oxidative stress and activation of inflammatory pathways, causing progressive kidney function decline and fibrosis. Blockade of the renin-angiotensin system or the sodium-glucose cotransporter is associated with cellular protection and slowing kidney function decline. Newly identified molecular pathways could provide the basis for the development of much-needed novel therapeutics.

Authors

Samer Mohandes, Tomohito Doke, Hailong Hu, Dhanunjay Mukhi, Poonam Dhillon, Katalin Susztak

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Figure 1

Changes of endothelial cells in diabetes.

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Changes of endothelial cells in diabetes. (Left) Early DKD is characteri...
(Left) Early DKD is characterized by increased VEGFA expression, VEGFA released by podocytes binds to VEGFR receptors (VEGFR1/2) expressed on glomerular endothelial cells. In addition, VEGFA may also affect the balance between the production of the vasoconstrictive factor endothelin-1 (ET-1) and the vasodilatory factor nitric oxide (NO). By binding to its receptors VEGFR1 and VEGFR2 on GEnCs, VEGFA can stimulate NO production and inhibit ET-1 expression, thus exerting protective effects on the glomerulus. Glomerular endothelial cells release endothelin, which can signal to nearby endothelial cells via endothelin receptors (ETRs). LRG1 potentiates TGFβ signaling to activate Smad pathways in endothelial cells. All 3 signals shown in this cell induce proliferation, migration, and/or angiogenesis in endothelial cells in the DKD glomerulus. (Right) Elevated glucose levels and dysregulated insulin signaling promote increased mitochondrial reactive oxygen species (ROS) levels. Nitric oxide can react with endothelial ROS to release peroxynitrates (ONOO-). Increased oxidative stress will lead to apoptosis of glomerular endothelial cells and enhanced endothelial permeability — changes mostly observed in late DKD. IR, insulin receptor; TGFβR, TGFβ receptor; GLUT4, insulin sensitive glucose transporter 4.