Calmodulin-dependent protein kinase II activation promotes kidney mesangial expansion in streptozotocin-induced diabetic mice

Alexei V Mikhailov; Yixi Liu; Heng-Jie Cheng; Jen-Jar Lin; Che Ping Cheng

doi:10.1016/j.heliyon.2022.e11653

Calmodulin-dependent protein kinase II activation promotes kidney mesangial expansion in streptozotocin-induced diabetic mice

Heliyon. 2022 Nov 14;8(11):e11653. doi: 10.1016/j.heliyon.2022.e11653. eCollection 2022 Nov.

Authors

Alexei V Mikhailov¹, Yixi Liu², Heng-Jie Cheng², Jen-Jar Lin³, Che Ping Cheng²

Affiliations

¹ Department of Pathology, Atrium Health Wake Forest School of Medicine, Winston-Salem, NC, USA.
² Cardiovascular Medicine, Atrium Health Wake Forest School of Medicine, Winston-Salem, NC, USA.
³ Department of Pediatrics, Atrium Health Wake Forest School of Medicine, Winston-Salem, NC, USA.

Abstract

Calcium-calmodulin-dependent protein kinase II (CaMKII) is upregulated in diabetes mellitus (DM), leading to the overproduction of collagen in the myocardium. We hypothesized that CaMKII plays a role in the development of diabetic nephropathy (DN). Streptozotocin (STZ) injection into FVB wild-type mice led to mild mesangial matrix expansion, reproducing an essential feature of early human DN. Mesangial matrix measurements were performed on trichrome-stained paraffin sections using a trainable segmentation method based on WEKA (Waikato Environment for Knowledge Analysis) Image J-Fiji plugin (TWS plugin), and the electron micrographs of the whole glomeruli stitched from individual 4800x partial glomerular images. Both methods demonstrated that the statistically significant mesangial matrix expansion seen in the diabetic mice was prevented by chronic pretreatment with KN-93, a small molecule CaMKII inhibitor. This study indicates a role for CaMKII in the development of mesangial alterations in diabetes and suggests a possible new therapeutic target.

Keywords: Calmodulin-dependent protein kinase II; Diabetic nephropathy; KN-93; Mesangium; Streptozotocin; WEKA Image J plugin.