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Abstract: SA-PO408

PACSIN2 Regulates the Inflammatory Response in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Bouslama, Rim, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Polianskyte-Prause, Zydrune, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Lehtonen, Eero, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Subashi, Yelin, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Lindfors, Sonja, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Karaman, Sinem, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Plomann, Markus, Universitat zu Koln, Köln, Germany
  • Lehtonen, Sanna H., Helsingin yliopisto, Helsinki, Uusimaa, Finland

Group or Team Name

  • Translational Metabolism, Sanna Lehtonen Lab.
Background

Diabetic kidney disease (DKD) is associated with hemodynamic and metabolic alterations including chronic low-level inflammation. Podocytes, the glomerular epithelial cells, are damaged by the inflammatory milieu in DKD via poorly understood mechanisms. Our study identifies protein kinase C and casein kinase substrate in neurons 2 (PACSIN2) as a new regulator of inflammation in the kidney.

Methods

This study relies on PACSIN2 knockout (KO) mice, in which we modeled DKD. We also used isolated human glomeruli and cultured human podocytes. We analyzed samples by quantitative Western blot, and immunofluorescence or immunohistochemical stainings.

Results

At the age of 12 months, compared to controls, PACSIN2 KO mice had paler kidneys, increased albumin to creatinine ratio, and altered glomerular vasculature. This coincided with increased circulating IL6, increased glomerular macrophage infiltration, and disrupted oxidative process in the glomeruli. Treatment of human glomeruli ex vivo with IL6 led to increased expression of PACSIN2. In cultured human podocytes, the expression and phosphorylation of PACSIN2 varied in response to inflammatory stimuli. PACSIN2 also interacted with NFkB and GSK3β depending on the stimulus. Diabetic PACSIN2 KO mice were lighter than diabetic controls, had lower glycaemia, lower albuminuria, and excreted less urine per 24h. We found no difference in macrophage infiltration and oxidative damage between diabetic WT and diabetic PACSIN2 KO mice. Nevertheless, the expression of NFkB and GSK3β was increased in glomerular lysates of diabetic PACSIN2 KO mice.

Conclusion

Our results indicate that lack of PACSIN2 alone causes kidney damage and increases inflammation in the glomeruli. In the context of DKD, lack of PACSIN2 improved metabolic and kidney parameters. Our study uncovers PACSIN2 as novel regulator of inflammation and highlights the contextual regulation of the inflammatory response in the glomeruli.

Funding

  • Private Foundation Support