Disruption of podocyte structure and function ultimately leads to chronic kidney disease. A new study by George Tsokos and colleagues reports a key role of calcium/calmodulin-dependent protein kinase type IV (CaMK4) signalling in podocyte dysfunction.

The researchers found that podocyte CaMK4 expression is upregulated in patients with lupus nephritis (LN) or focal segmental glomerulosclerosis (FSGS) and in mouse models of podocyte injury. To specifically inhibit podocyte CaMK4 in mice, they used nanolipogels loaded with a CaMK4 inhibitor and tagged with either anti-podocin or anti-nephrin antibodies. Treatment with these nanolipogels protected mice against non-immune podocyte injury induced by polysaccharide or adriamycin (a model of FSGS) and prevented podocyte foot process effacement and the development of LN in lupus-prone mice.

“Our most exciting finding was that when we inhibited podocyte CaMK4 in lupus-prone mice, we did not see any dense deposits in the glomeruli despite the fact that autoimmunity was rampant in the periphery,” says Tsokos. “My interpretation of this observation is that if podocytes keep their structural and functional integrity, deposition of immune complexes does not occur. This concept upsets the classic dogma that immune complexes deposit indiscriminately and cause inflammation.”

Further investigations indicated that CaMK4 suppresses nephrin expression and increases podocyte motility and actin cytoskeleton remodelling via a mechanism involving increased expression of activated Rac1 and synaptopodin degradation. By contrast, podocyte-specific inhibition or silencing of CaMK4 preserves synaptopodin expression and protects against damage to actin fibres and the cytoskeleton.

“CaMK4 is a molecule of pathogenic importance for immune and non-immune kidney diseases,” concludes Tsokos. “Our findings could have repercussions for the treatment of patients with LN and FSGS.”