Abstract: TH-OR063

Calcium/Calmodulin-Dependent Kinase IV Compromises Podocyte Function in Autoimmune and Non-Autoimmune Kidney Diseases

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Maeda, Kayaho, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
  • Otomo, Kotaro, Keio University School of Medicine, Tokyo, Japan
  • Yoshida, Nobuya, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
  • Bickerton, Sean Douglas, Yale School of Medicine, New Haven, Connecticut, United States
  • Fahmy, Tarek, Yale School of Medicine, New Haven, Connecticut, United States
  • Tsokos, Maria, Harvard Medical School, Boston, Massachusetts, United States
  • Tsokos, George C, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
Background

Podocyte dysfunction is a common feature of renal injury in autoimmune or non-autoimmune renal diseases and the good target of proteinuric kidney diseases. We previously reported that calcium/calmodulin-dependent kinase IV (CaMK4) was upregulated as a result of exposure to IgG from the patients with lupus nephritis (LN). Since podocytes from patients and mice with lupus have increased levels of CaMK4 linked to decreased nephrin expression, we considered that targeted delivery of a CaMK4 inhibitor (KN93) to podocytes should preserve podocyte function.

Methods

We treated lupus-prone MRL.lpr mice starting at 8 weeks age, mice injected lipopolysaccharide (LPS) or adriamycin with anti-podocin or nephrin tagged nanolipogels (nlg) loaded with KN93 intraperitonealy (i.p.). We also used immortalized differentiated human podocytes to examine the actin structure and function under LPS or lupus IgG treatment.

Results

Podocytes from lupus-prone or LPS-or adriamycin-treated mice and patients with LN or focal segmental glomerulosclerosis (FSGS) displayed increased expression of CaMK4. Targeted delivery of KN93 to podocytes suppressed proteinuria, immune complex deposition and crescent formation in lupus-prone mice and proteinuria in mice with LPS-or adriamycin-induced podocyte injury by preserving podocyte structure, nephrin and synaptopodin expression. In animals exposed to adriamycin, podocyte-specific delivery of KN93 prevented and reversed renal disease. Similarly, CaMK4 deficiency also protected from those podocyte injuries. Inhibition or silencing of CaMK4 protected from LPS-induced the actin cytoskeleton injury and synaptopodin degradation in human podocytes. Activated CaMK4 interacted with 14-3-3β and disrupted the binding of synaptopodin with 14-3-3β leading to actin cytoskeleton rearrangement of podocytes.

Conclusion

We conclude that inhibition of CaMK4 preserves podocyte structure and function and targeted delivery of a CaMK4 inhibitor to podocytes should have therapeutic value in lupus nephritis and podocytopathies including FSGS.

Funding

  • NIDDK Support