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Molecular mechanisms of diabetic kidney disease
Kimberly Reidy, … , Thomas Hostetter, Katalin Susztak
Kimberly Reidy, … , Thomas Hostetter, Katalin Susztak
Published June 2, 2014
Citation Information: J Clin Invest. 2014;124(6):2333-2340. https://doi.org/10.1172/JCI72271.
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Review Series

Molecular mechanisms of diabetic kidney disease

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Abstract

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. DKD is a prototypical disease of gene and environmental interactions. Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. Blood pressure control, especially with medications that inhibit the angiotensin system, is the only effective way to slow disease progression. While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. Concerted clinical and basic research efforts will be needed to understand DKD pathogenesis and to identify novel drug targets.

Authors

Kimberly Reidy, Hyun Mi Kang, Thomas Hostetter, Katalin Susztak

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Figure 3

The central role of podocytes in DKD.

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The central role of podocytes in DKD.
(A) Podocyte foot processes, the G...
(A) Podocyte foot processes, the GBM, and endothelial cells form a tight filtration barrier in the glomerulus. (B) Podocytes are lost due to apoptosis and detachment. Hyperglycemia-induced ROS release and PARP activation plays an important role in the process. (C) The remaining podocytes enlarge, reorganize their actin cytoskeleton, and spread (foot process effacement) to cover the GBM. Podocyte foot process effacement is associated with the activation of small GTP binding proteins (Rho, Rac, Cdc) and integrins. AMPK and mTOR activation contribute to podocyte enlargement. 4EBP1, 4E binding protein 1; ILK, integrin-linked kinase. (D) Increased, sustained activation of developmental pathways, Notch and Wnt, and canonical β-catenin activation cause loss of expression of markers associated with differentiated cell types (dedifferentiation).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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