Podocytes, specialized cells named for their foot processes, play an essential role in kidney function. These cells line the capillaries of the glomerulus, the functional unit of filtration within the kidney, and are connected by junctions that aid in filtration called slit diaphragms. Slit diaphragms are composed of a complex network of proteins and allow waste to be removed while retaining proteins in the blood.
Injury to podocytes is characteristic of both autoimmune and nonautoimmune kidney disease. Prolonged damage to podocytes results in chronic kidney disease, a progressive loss of kidney function with no known cure. A study in The Journal of Clinical Investigation by George C. Tskokos and his team at Beth Israel Deaconess Medical Center demonstrates that Calcium/Calmodulin-Dependent Protein Kinase IV (CaMK4) is overexpressed in injured podocytes. This makes CaMK4 a promising therapeutic target for treatment of chronic kidney disease.
Tskokos and his team began their research by comparing levels of CaMK4 in podocytes from patients with lupus nephritis (an autoimmune kidney disease) as well as focal segmental glomerulosclerosis (a nonautoimmune kidney disease) to CaMK4 levels in podocytes from healthy individuals. They found that CaMK4 is overexpressed in podocytes from patients with kidney disease. These findings extended to mouse models where both mice with autoimmune kidney disease and mice exposed to podocyte damaging agents showed increased CaMK4 levels.
The researchers next asked if inhibition of CaMK4 could prevent kidney disease in lupus-prone mice, a model for autoimmune kidney disease. Nanolipogels — transport particles used to deliver targeted drugs — carrying a CaMK4 inhibitor were coated with Bioss biotin-conjugated podocin or biotin-conjugated nephrin antibodies allowing for targeted delivery of the drug to podocytes.
Tskokos emphasized the utility of using nanolipogels coated in antibody to deliver inhibitor specifically to podocytes.
“The inhibition that we accomplished here requires ten percent, or even less, of the dose of CaMK4 inhibitor that would be otherwise needed if it were to be administered systemically,” he said in a video interview with JCI.
The targeted treatment showed promising results. Mice treated with nanolipogels containing inhibitor, but not those treated with empty nanolipogels, were protected from kidney disease. When the glomeruli from the treated mice were examined, researchers found that no immune deposits were present, despite the fact that there were ample immune deposits in the surrounding area. This finding suggests that functional podocytes do not allow for deposition of immune complexes the glomerulus.
Figure 3 from study in The Journal of Clinical Investigation shows reduced kidney disease development in the lupus mouse model after injection with anti-podocin or anti-nephrin antibody–coated nanolipidgels.
Targeted delivery of the CaMK4 inhibitor to podocytes was also tested in nonautoimmune models of podocyte damage. Mice treated with drugs to induce podocyte damage were able to escape kidney disease when also treated with nanolipogels containing CaMK4 inhibitor. Even more encouraging for application in the clinic, CaMK4 inhibitors were able to reverse existing podocyte damage in mice.
Further study of CaMK4 revealed the mechanism by which CaMK4 inhibition protects podocytes from damage. CaMK4 has a role in podocyte mobility and actin cytoskeleton remodeling. The actin cytoskeleton is essential for the formation of podocyte foot processes and maintenance of the slit diaphragm. Inhibition of CaMK4 with a chemical inhibitor or silencing of CaMK4 with siRNA allowed podocytes to maintain their actin structure in the presence of podocyte damaging agents. This is accomplished by an increase in nephrin, a protein critical to the slit diaphragm and synaptopodin, an actin-associated protein integral to podocyte function.
The finding that CaMK4 overexpression underlies podocyte dysfunction in both autoimmune and nonautoimmune kidney disease brings the promise of new treatment chronic kidney disease patients. In the future, targeted CaMK4 inhibition might be used to treat this devastating disease in humans. Researchers could also extend these studies to chronic kidney disease caused by diabetes or high blood pressure.
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Lead photo courtesy of Beth Israel Deaconess Medical Center, http://cvvr.hms.harvard.edu