Diabetic fibrosis

Abstract

Diabetes-associated morbidity and mortality is predominantly due to complications of the disease that may cause debilitating conditions, such as heart and renal failure, hepatic insufficiency, retinopathy or peripheral neuropathy. Fibrosis, the excessive and inappropriate deposition of extracellular matrix in various tissues, is commonly found in patients with advanced type 1 or type 2 diabetes, and may contribute to organ dysfunction. Hyperglycemia, lipotoxic injury and insulin resistance activate a fibrotic response, not only through direct stimulation of matrix synthesis by fibroblasts, but also by promoting a fibrogenic phenotype in immune and vascular cells, and possibly also by triggering epithelial and endothelial cell conversion to a fibroblast-like phenotype. High glucose stimulates several fibrogenic pathways, triggering reactive oxygen species generation, stimulating neurohumoral responses, activating growth factor cascades (such as TGF-β/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs) and stimulating the AGE-RAGE axis, and upregulating fibrogenic matricellular proteins. Although diabetes-activated fibrogenic signaling has common characteristics in various tissues, some organs, such as the heart, kidney and liver develop more pronounced and clinically significant fibrosis. This review manuscript summarizes current knowledge on the cellular and molecular pathways involved in diabetic fibrosis, discussing the fundamental links between metabolic perturbations and fibrogenic activation, the basis for organ-specific differences, and the promises and challenges of anti-fibrotic therapies for diabetic patients.

Keywords: Diabetes; Extracellular matrix; Fibroblast; Fibrosis; Growth factors; Matricellular proteins.

Figure 1:. Fibrotic changes in animal models of diabetes.

Obese diabetic leptin-resistant db/db mice exhibit fibrotic changes in several different organs, including the kidney (A–B) and the heart (C–D). A–B: Representative images from kidney sections from a lean (A) and a db/db mouse at 6 months of age stained with PicroSirius red to label collagen fibers. Please note the mild fibrosis involving the glomerulus (arrowhead) and the tubulointerstitium (arrows) in db/db mice. C–D: Representative images from left ventricular myocardial sections from a lean (C) and a db/db mouse (D) at 6 months of age, stained with PicroSirius red and visualized under polarized microscopy. The db/db mouse shows modest expansion of the collagen network in perivascular (arrows) and interstitial areas (arrowheads). In contrast to the extensive fibrosis noted in human diabetic patients, changes in rodent models of diabetes are generally mild. This likely reflects the absence of atherosclerotic disease and other comorbid conditions that often accompany diabetes in human patients, and the young age of the experimental animals.

Figure 2:. Effects of high glucose on fibroblast activity and function.

The fibrogenic effects of hyperglycemia may involve several distinct mechanisms, including activation of neurohumoral pathways, induction and activation of growth factors (such as TGF-β and PDGFs), stimulation of pro-inflammatory cytokines (such as TNF-α and IL-1β), generation of AGEs, induction of surface integrins and secretion of matricellular proteins (such as TSP-1, SPARC and CCN2). A central pathway involved in fibroblast activation in response to high glucose involves the generation of reactive oxygen species (ROS). Moreover, high glucose may disrupt DNA repair, thus accentuating the effects of ROS on DNA damage and promoting cellular senescence, inflammatory activation and fibrosis. In response to high glucose fibroblasts proliferate, and undergo activation, secreting collagens, proteases and antiproteases involved in matrix remodeling, and matricellular proteins. Although in vitro studies have suggested that high glucose may enhance fibroblast to myofibroblast conversion, to what extent diabetic fibrosis is dependent on myofibroblasts (vs. activated fibroblasts) remains unknown.

Figure 3:. The link between hyperglycemia and activation of the TGF-β cascade.

High glucose potently stimulates fibrogenic TGF-β-mediated cascades through several distinct mechanisms involving increased TGF-β synthesis, enhanced activation through upregulation of matricellular proteins (such as TSP-1), activation of angiotensin II, induction of pro-inflammatory cytokines (such as IL-1β and TNF-α) which stimulate TGF-β synthesis, and increased surface expression of TGF-β receptors. In diabetic tissues, TGF-β exerts its fibrogenic effects predominantly through activation of Smad3; the role of Smad-independent pathways remains poorly understood. Although TGF-β exerts potent fibrogenic actions through Smad-dependent regulation of gene expression, some of its fibrogenic actions may be mediated through downstream secreted effectors, such as CCN2 and IL-11.

Figure 4:. The basis for the increased susceptibility of the kidney, heart and liver to diabetes-associated fibrosis.

Diabetes-associated hyperglycemia, and lipotoxicity exert pro-fibrotic actions on many tissues; however, certain organs such as the liver (LI), kidney (K) and heart (H) seem to exhibit accentuated fibrogenic activation in comparison to other organs, such as the eye (E) and the lung (LU). Several mechanisms may explain the organ-specific fibrotic remodeling in diabetic subjects. First, parenchymal cells in the liver, kidney and heart may be more susceptible to metabolic injury, thus activating secondary inflammatory and fibrogenic reparative responses. Second, organ-specific differences in the cellular composition and growth factor responsiveness of interstitial cells and immune cells may account for higher fibrogenic potential. Third, as oxidative stress is a major driver of fibrotic responses in diabetes, organs with higher endogenous antioxidant mediators may be less susceptible to fibrosis. Finally, organs lacking regenerative capacity (such as the heart) may develop fibrosis in response to the insidious loss of parenchymal cells associated with chronic severe metabolic injury. This figure was created using images from Servier Medical Art ((http://smart.servier.com).