Molecular mechanisms of diabetic kidney disease
Kimberly Reidy, Hyun Mi Kang, Thomas Hostetter, Katalin Susztak
Kimberly Reidy, Hyun Mi Kang, Thomas Hostetter, Katalin Susztak
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Molecular mechanisms of diabetic kidney disease

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 2

Dysregulated metabolism is a key factor in DKD initiation.

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Dysregulated metabolism is a key factor in DKD initiation. Animal and ce...
Animal and cell culture experiments indicate that increased intracellular glucose metabolism by the polyol and hexosamine pathways occurs in complication-prone cell types in diabetes. There is also excessive activation of the PKC pathway and non-enzymatic glucose oxidation to advanced glycation end products (AGE). Mitochondrial oxidative phosphorylation and ROS release production are increased. Changes in intermediate metabolism can have a sustained effect on gene expression by reprogramming the epigenome. Data from the cancer metabolism field indicates that products of intermediate metabolism serve as substrates for different chromatin modifier enzymes, including histone acetyltransferases (HAT), sirtuins, and histone and DNA methyltransferases. Excessive activation of the chromatin-modifying enzyme PARP1 has also been described in DKD. Ac-CoA, acetyl coenzyme A; F-6-P, fructose 6-phosphate; G-3-P, glucose 3-phosphate; OGT, O-GlcNAc transferase; TCA, tricarboxylic acid.