Evidence reported in the October issue of Cell Metabolism, a Cell Press publication, offers a completely new explanation for why people with diabetes account for more than half of all patients requiring dialysis or kidney transplantation. It appears that insulin has a significant influence on the structure and proper function of a particular group of very specialized cells, known as podocytes, that are integral to the kidney's ability to do its job filtering blood.
"We've found that when you lose insulin signaling in the podocytes, the filter is not maintained," said Richard Coward of the University of Bristol. "Insulin action on the podocyte is really important to kidney function."
In the past, diabetic kidney failure had been considered a result of the toxic effects of high blood-sugar levels on cells of the kidney. That may still be true, Coward said, but the new findings suggest that insulin resistance of podocytes is key. He suggests that general insulin-sensitizing drugs or drugs specifically designed to restore insulin sensitivity to podocytes might offer new treatments for the most common cause of kidney failure in the world.
Podocytes are quite remarkable cells that look a lot like octopuses, Coward explained. "They have a massive cell body with processes extending from them" like the legs of an octopus. Those cells form a lace-like structure that is important to preventing albumin proteins from leaking out of the bloodstream and into the urine. That leakage is used as an early sign of kidney disease, and it generally worsens over time.
The researchers had earlier shown that podocytes are uniquely sensitive to insulin. To find out what influence that insulin sensitivity might have on kidney function in the new study, they generated mice lacking insulin receptors only in their podocytes. Sure enough, those animals began to show protein in their urine along with other features characteristic of diabetic kidney disease. That was despite the fact that the animals weren't diabetic and had normal blood sugar levels.
Further examination found that insulin activity in podocytes causes them to remodel themselves. Coward said that makes sense in that podocytes "are not static cells. They move actively and contract or remodel themselves." He suspects that the cells do this in response to insulin because they need to "brace themselves for an increased work load after a meal."
Coward said there is already some evidence that traditional insulin-sensitizing drugs can help protect against kidney disease in diabetic animals. Insulin sensitizers that specifically target the podocyte might be good treatments for preventing kidney failure, he said, especially given that very sensitive urine tests can now identify a breakdown in the kidneys early.
The researchers include Gavin I. Welsh, University of Bristol, Bristol, UK; Lorna J. Hale, University of Bristol, Bristol, UK; Vera Eremina, University of Toronto, Toronto, Ontario, Canada; Marie Jeansson, University of Toronto, Toronto, Ontario, Canada; Yoshiro Maezawa, University of Toronto, Toronto, Ontario, Canada; Rachel Lennon, University of Bristol, Bristol, UK; Deborah A. Pons, University of Bristol, Bristol, UK; Rachel J. Owen, University of Bristol, Bristol, UK; Simon C. Satchell, University of Bristol, Bristol, UK; Mervyn J. Miles, University of Bristol, Bristol, UK; Christopher J. Caunt, University of Bristol, Bristol, UK; Craig A. McArdle, University of Bristol, Bristol, UK; Hermann Pavenstadt, University Clinics Muenster, Muenster, Germany; Jeremy M. Tavare, University of Bristol, Bristol, UK; Andrew M. Herzenberg, University Health Network and University of Toronto, Ontario, Canada; C. Ronald Kahn, Joslin Diabetes Center and Harvard Medical School, Boston, MA; Peter W. Mathieson, University of Bristol, Bristol, UK; Susan E. Quaggin, University of Toronto, Toronto, Ontario, Canada; Moin A. Saleem, University of Bristol, Bristol, UK; and Richard J.M. Coward, University of Bristol, Bristol, UK, University of Toronto, Toronto, Ontario, Canada.
- Gavin I. Welsh, Lorna J. Hale, Vera Eremina, Marie Jeansson, Yoshiro Maezawa, Rachel Lennon, Deborah A. Pons, Rachel J. Owen, Simon C. Satchell, Mervyn J. Miles, Christopher J. Caunt, Craig A. McArdle, Hermann Pavenstδdt, Jeremy M. Tavarι, Andrew M. Herzenberg, C. Ronald Kahn, Peter W. Mathieson, Susan E. Quaggin, Moin A. Saleem, Richard J.M. Coward. Insulin Signaling to the Glomerular Podocyte Is Critical for Normal Kidney Function. Cell Metabolism, Volume 12, Issue 4, 329-340, 6 October 2010 DOI: 10.1016/j.cmet.2010.08.015
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