Editors' ChoiceNephropathy

New Cause for Diabetic Nephropathy

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Science Translational Medicine  13 Oct 2010:
Vol. 2, Issue 53, pp. 53ec158
DOI: 10.1126/scitranslmed.3001767

The current exhibition at the New York Historical Society on the discovery of insulin reminds us that injectable insulin was isolated a lifetime ago—almost 90 years. But research on diabetes, with its myriad medical complications, continues to surprise. Until now, researchers believed that diabetes-associated kidney failure—diabetic nephropathy (DN)—was caused by the toxic effects of high blood sugar. However, a new study demonstrates that insulin resistance alone is sufficient to cause a form of kidney failure in mice that closely resembles DN in patients.

The kidney serves as a reprocessing apparatus that filters waste products and excess water from the blood. The filtering component of the kidney consists of podocytes and glomerular endothelial cells, which in the process of forming urine, weed out proteins and allow small molecules such as sugars, salts, and water to pass. If these cells are damaged, the filter becomes leaky, and protein loss ensues, eventually leading to kidney failure. DN is characterized by an increase in protein in the urine (proteinuria) and is the cause of more than half of all cases of end-stage renal disease that require dialysis or a kidney transplant. In diabetic patients, the kidneys process blood with high concentrations of glucose, and glucotoxicity was thought to give rise to DN. However, diabetes is often associated with insulin resistance, especially in the most common form of the disease, which is referred to as adult-onset or type 2 diabetes. It had not been seriously considered that insulin resistance could be an independent risk factor for DN because patients with insulin-deficient (type 1) diabetes are mostly insulin-sensitive and also suffer from DN. This point of view has now changed because Welsh et al. have shown that insulin resistance in mouse podocytes can cause a DN-related type of kidney failure in the absence of high blood sugar.

These authors first studied the effects of insulin on mouse podocytes in vitro; they noticed that insulin signaling did indeed occur, and glucose uptake by the cells was stimulated, which is a common physiological effect of insulin. On the basis of these findings, they created knockout mice that failed to express the insulin receptor protein specifically in podocytes. At first, the knockout mouse phenotype seemed innocuous. Glucose homeostasis was not impaired, and the kidneys appeared to be morphologically and functionally normal at 3 weeks of age. However, at 5 weeks of age, the insulin receptor knockout mice developed progressive proteinuria and exhibited histological signs of DN. The obliteration of insulin signaling appeared to induce reorganization of the actin cytoskeletons of the podocytes in the knockout mice, which is a probable explanation for the impairment of podocyte morphology and function. As with all knockout models that carry a life-long rather than a conditional defect, the possibility that the progressive damage of the podocytes results from developmental defects cannot be excluded, even though the kidney appeared normal at 3 weeks of age. Elimination of this possibility will require a mouse model in which the reduction in insulin receptor expression is inducible after birth. However, if confirmed these findings can lead to a change in the way physicians manage DN; indeed, it may be possible to prevent DN through the use of insulin-sensitizing agents, even in patients with type 1 diabetes.

G. I. Welch et al., Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 12, 329–340 (2010). [Abstract]

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