Insulin is key to kidney disease

A form of kidney disease may result from defective insulin signaling, challenging conventional wisdom

Oct 5, 2010
Jef Akst
Diabetic kidney disease likely results from defective insulin signaling in the kidneys, contradicting long-standing suspicions, according to findings appearing online today (October 5) in Cell Metabolism.
A renal biopsy showing nodular glomerulosclerosis
in a case of diabetic nephropathy.

Image: Wikimedia commons,
Scientists have long attributed this type of kidney disease -- the leading cause of renal failure -- to high glucose levels in the blood and defects in the kidney microvasculature.The study "suggests there's a direct effect of insulin" on epithelial cells in the kidney, "which is really a new idea," said nephrologist linkurl:Thomas Coffman; of Duke University School of Medicine, who was not involved in the research. "I'm sure it will be a highly cited paper."Diabetes causes numerous health problems, including a form of kidney disease known as diabetic nephropathy (DN). DN is characterized by protein in the urine, enlarged kidneys, and abnormalities in the glomeruli, specialized capillaries where the urine filtration process begins, and other parts of the kidney. Researchers most often attribute the disease to defects in the microvasculature of the kidneys as a result of high blood glucose levels, which are known to be toxic to a variety of cell types. But growing evidence suggests that another cell type may be involved -- epithelial cells known as podocytes. Furthermore, some people with insulin resistance accumulate protein in their urine, even when glucose is normal. To investigate the role of podocytes and insulin signaling in the development of DN, a team led by molecular biologist and pediatrician linkurl:Richard Coward; of the University of Bristol in the UK examined two knockout mice models whose podocytes lacked the insulin receptor. Within 5 weeks of birth, the mice had developed abnormalities in their kidneys characteristic of human DN and protein had started accumulating in their urine, despite normal blood glucose levels. Their symptoms continued to worsen over the next 8 weeks."Our work suggests [DN] is not necessarily directly related to high glucose, but probably an insensitivity of that cell to insulin," Coward said. The mice were normal at birth, however, he noted, so insulin signaling in podocytes "doesn't seem to be that important for [kidney] development." Notably, not all the symptoms of DN were present in the KO mice, suggesting other mechanisms may be important for the disease pathogenesis. To examine how insulin signaling affects podocytes, the team examined the cells in vitro while adding varying amounts of insulin. They found that insulin alters the actin cytoskeletons of the cells, resulting in overall structural changes, including the retraction of cell projections that play a role in urine filtration. This restructuring process appears necessary to the normal function of the kidneys."What we think happens is that these cells are really dynamic, constantly remodeling and moving," Coward said. "With insulin, every time you have a meal, there's remodeling to brace itself for the increase in filtration load to the kidney." When insulin signaling is impaired, the cells fail to remodel, affecting their ability to filter proteins from the urine.This is not the first paper to expand insulin's role in disease -- scientists are finding more and more examples of major illnesses that may result from disruptions in the insulin signaling cascade. (See The Scientist's linkurl:recent feature; for the wide-reaching implications of this pathway.)The results may also provide novel drug targets for the prevention or treatment of DN, suggested Coffman, who wrote an accompanying perspective. "This study suggests that the pathway of insulin [signaling] in epithelial cells is going to be important," he told The Scientist. "It does raise that as a pathway that could be targeted and probably should be targeted."G.I. Welsh, et al., "Insulin signaling to the glomerular podocyte is critical for normal kidney function," Cell Metabolism, 12:329-40, 2010.
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