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Review
. 2014 Jun;124(6):2333-40.
doi: 10.1172/JCI72271. Epub 2014 Jun 2.

Molecular mechanisms of diabetic kidney disease

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

Molecular mechanisms of diabetic kidney disease

Kimberly Reidy et al. J Clin Invest. 2014 Jun.

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.

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Figures

Figure 1
Figure 1. Pathological lesions of DKD.
The normal healthy glomerulus includes afferent arterioles, capillary loops, endothelial cells, basement membrane, podocytes, parietal epithelial cells, and tubule epithelial cells and is impermeable to albumin. In contrast, the diabetic glomerulus displays arterial hyalinosis, mesangial expansion, collagen deposition, basement membrane thickening, podocyte loss and hypertrophy, albuminuria, tubular epithelial atrophy, accumulation of activated myofibroblasts and matrix, influx of inflammatory cells, and capillary rarefaction. Also shown are a normal healthy human glomerular section and a kidney section from a sample with DKD (PAS stained). Original magnification, ×400.
Figure 2
Figure 2. Dysregulated metabolism is a key factor in DKD initiation.
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.
Figure 3
Figure 3. The central role of podocytes in DKD.
(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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