Parasitoid wasp venom elevates sorbitol and alters expression of non-canonical sorbitol metabolic genes in human kidney cells

Venom from the parasitoid wasp Nasonia vitripennis dramatically elevates sorbitol levels in its natural fly hosts. In humans, sorbitol elevation is associated with complications of diabetes. Here we demonstrate that venom also induces this disease-relevant phenotype in human cells, and investigate possible pathways involved. Key findings are that (a) low doses of Nasonia venom elevate sorbitol levels in human renal mesangial cells (HRMCs) without changing glucose or fructose levels, (b) venom is a much more potent inducer of sorbitol elevation than is glucose, (c) low venom doses significantly alter expression of genes involved in sterol and alcohol metabolism, transcriptional regulation, and chemical/stimulus response, (d) although expression of the key sorbitol pathway gene aldose reductase (AR) is not altered by venom, but (d) venom elevates expression of a related gene implicated in diabetes complications (AKR1C3) as well as the fructose metabolic gene (GFPT2). Although elevated sorbitol is accepted as a major contributor to secondary complications of diabetes, in particular kidney disease, the molecular mechanism of regulation and contribution relative to hyperglycemia is not fully understood. Our findings suggest that genes other than AR could contribute in vivo to sorbitol elevation, and more broadly illustrate the potential of parasitoid venoms for medical application.