Cation channels of the TRPC family contribute to development of nephropathy and retinopathy in the STZ model

The pathogenesis of hyperglycemia-dependent diabetic longterm complications involves the accumulation of reactive metabolites which were recently shown to affect cation channels such as Nav_1.8 and TRPA1 channels as targets and essential effector molecules in signaling pathways involved in the disease process.

Likewise, other members of the TRP cation channel family including members of TRPC and TRPM family are regulated in their acitivity by reactive metabolites including reactive oxygen species (ROS). We performed a screening using several TRPC- and TRPM-deficient mouse lines to elucidate a causal relevance of such cation channels for development of diabetic retinopathy and nephropathy. Nanostring-based expression analysis revealed abundant expression of TRPC1, TRPC3, TRPC4 and TRPC6 in the mouse retina with TRPC6 being upregulated under diabetic conditions, and STZ treatment-induced increase of acellular capillaries as well as pericyte loss was significantly reduced in mice lacking four of the seven TRPC cation channel proteins (TRPC QKO mice). Although TRPC QKO mice showed comparable levels of hyperglycaemia (HbA1c measurements), the STZ treatment-evoked increase in mesangial matrix area was significantly reduced. Accordingly, measurements of glomerular filtration using FITC-labeled Sinistrin showed protection with regard to STZ-evoked hyperfiltration in TRPC QKO. Recent findings about the regulation of TRPC channels by reactive metabolites in primary mesangial and endothelial cells will be discussed. Taken together cation channels of the TRPC family essentially contribute to the development of diabetic longterm complications in the STZ model possibly by interference with signaling pathways triggered by reactive metabolites.