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 2

Mechanisms of podocyte dysfunction in DKD.

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Mechanisms of podocyte dysfunction in DKD. (Left) Early stages of DKD le...
(Left) Early stages of DKD lead to effacement of podocyte foot processes; multiple pathways contribute to the reorganization of the actin cytoskeleton, including TRPC6-mediated calcium influx activated by angiotensin (ANG) signaling, changes in nephrin endocytosis, and LKB1-associated signaling. In addition, mechanical stress pathways (YAP/TAZ), as well as thickening of the glomerular basement membrane (GBM), can induce integrin and downstream integrin linked kinase (ILK) activation. (Middle) Podocyte hypertrophy also characterizes the early stages of DKD. Growth factor and insulin signaling activates PI3K and mTOR pathways that regulate protein synthesis and cell growth. (Right) Later disease stages are characterized by podocyte death and dedifferentiation. The endoplasmic reticulum enzyme sterol-O-acetyltransferase-1 (SOAT1) facilitates the formation of cholesterol-enriched lipid droplets in podocytes. Dysregulated insulin signaling and high glucose levels trigger oxidative stress and apoptosis. NLRP3-mediated pyroptosis also contributes to podocyte loss. ABCA1, ATP-binding cassette A1; AT1R, angiotensin II receptor type 1; TRPC6, transient receptor potential channel 6.