CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy

Abstract

Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications, Instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM Kinase II δ (CaMKIIδ) that is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle but also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs.

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

“…However, our results differ from a previous study reporting that CaM Kinase II-δ is required for the development of diabetic hyperglycemia and retinopathy but not for nephropathy [ 48 ]. Several factors may contribute to this difference.…”

Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice

“…FITC-labeled WT1 (green) and DAPI (nuclei, blue) were used. WT1 is mainly expressed on the nucleus of glomerular podocytes, and the specific positive staining is indicated by the arrows 48 . Original magnification ×1000, Scale bar: 10 µm.…”

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

“…Indeed, an increasing body of evidence is emerging that challenges the prevailing idea that reducing hyperglycemia is a unifying target in diabetes treatment, particularly for the prevention of long-term complications. The development of diabetic neuropathy, for instance, has been shown to be independent of normalizing hyperglycemia 61 . Our previous study also indicates that a significant extension of lifespan of mice with pancreatic β-cell loss and ID could be achieved without dramatic improvements in hyperglycemia 42 .…”