Diseased renal glomeruli are getting soft. Focus on "Biophysical properties of normal and diseased renal glomeruli".

TISSUES AND CELLS are characterized by mechanical properties that are variously described as elasticity, deformability, or stiffness, which are critical components in determining their normal structure and function (reviewed in Ref. 25). However, biologists and physicians are not used to thinking of mechanical signals as having a primary role equivalent to biochemical signals in normal biology and disease. Appreciation of the importance of mechanical factors in biology, including the elastic properties of tissues and cells, has increased over the past 20 years. In many situations, mechanical factors, in collaboration with biochemical signals, have primary roles in the development and maintenance of tissue phenotype as well as disease. In this context, change from a soft (deformable 0.2 kPa) to a hard/dense (nondeformable 4 kPa) breast tissue represents a major risk factor for developing breast cancer, and females with higher levels of breast density are at higher risk for developing breast cancer (1). This is probably due to the fact that normal breast cells exposed to a stiff/hard extracellular environment (i.e., collagen-rich environment) lose their epithelial morphology as well as the ability to form acini and tend acquire a more invasive/malignant phenotype (18). Another example of how the elasticity of the surrounding environment determines cell behavior is offered by the liver. The elastic modulus of normal liver is 0.5 kPa but can increase to 15 kPa in the course of injury or fibrosis (6, 23). As a consequence of increased matrix stiffness, hepatocytes, stellate cells, and portal fibroblasts divide more rapidly, thus contributing to the disease (15). A third example is from studies showing that neurons grow selectively when brain cortical cells are plated on soft substrates (0.15–0.3 kPa) (7, 8). However, when the same cells are plated on more rigid substrate (2 kPa), glia grow selectively (7, 8). Thus it is clear that the mechanical properties of the extracellular environment are important contributors to cell lineage, cell proliferation, cell migration/invasion, and ultimately disease phenotypes. In addition to extracellular elasticity, intracellular elastic properties play a key role in determining cell fate and function. Intracellular elastic properties are determined by factors that include: 1) the amount and form of polymerized actin, 2) the extent and nature of polymerized actin cross-linking by other proteins ( -actinin), 3) adhesion to substrate (focal adhesions, type of matrix receptors), and 4) the ability of a cell to develop internal tension (changes in the organization of the cytoskeleton, adhesion complexes, microfilaments, and myosin). Changes in any of these factors might contribute to alterations in intracellular elastic properties, cell behavior, fate, and ultimately tissue damage (reviewed in Ref. 5). Little is known about the biomechanical properties of healthy and diseased kidneys. Although pathologists know that kidneys from patients with end-stage kidney disease are hard and dense, and nephrologists who perform biopsies know that often a diseased kidney repels a biopsy needle, it is unknown whether changes in stiffness or elasticity directly contribute to the pathogenesis of kidney disease. The glomerulus, the filtering unit of the kidney, is a frequent site of injury and progressive disease. Glomeruli consist of 1) specialized fenestrated endothelial cells; 2) mesangial cells; 3) terminally differentiated visceral cells (podocytes); and 4) the glomerular basement membrane (GBM) that separates podocytes from endothelial cells (see also Fig. 1A). In humans, the kidneys filter 1.5 liter of blood per minute, which means the glomeruli are exposed to pulsatile flow and must have the ability to adjust and/or quickly respond to changes in blood volume and/or pressure to maintain a constant filtration rate. With loss of renal mass, glomerular capillary pressures increase, and this increase in pressure appears to be related directly to injury of presumably structurally normal capillaries. A number of human genetic glomerular diseases and mouse models of genetic disease have been described that could potentially be caused by changes in the mechanical/elastic properties of either the extracellular environment or glomerular cells. Many of the genes mutated in these renal diseases (e.g., the 3 or 5 chain of collagen IV, -actinin-4, or podocytespecific proteins that alter cell-cell junctions) affect the structure of either the GBM or the cytoskeleton of glomerular cells (9, 11, 13, 19, 20) (Fig. 1B). No evidence exists that the early stages of these diseases are characterized by abnormal (increased) glomerular capillary blood pressure or flow. Therefore, glomerular injury in these as well as other conditions [e.g., HIV-associated nephropathy characterized by altered podocyte structure (21)], involves abnormal, presumably weakened, structures in the presence of normal hemodynamic forces, and strongly suggests that in these conditions, cellular and tissue mechanical abnormalities may have a fundamental role in glomerular injury. If altered mechanical characteristics of glomeruli contribute to disease, glomeruli should have specific mechanical characteristics with elastic moduli that need to be kept constant to allow proper function of these filtering units and maintain the differentiated state of glomerular cells. Whether these biophysical properties change in the course of glomerular disease and whether the elastic moduli of diseased glomeruli are increased or decreased compared with normal glomeruli or, in other words, whether they are less or more deformable following Address for reprint requests and other correspondence: A. Pozzi, Dept. of Medicine, Vanderbilt Univ., Medical Center North, B3115, Nashville, TN 37232-2372 (e-mail: [email protected]). Am J Physiol Cell Physiol 300: C394–C396, 2011; doi:10.1152/ajpcell.00511.2010. Editorial Focus