3.1.1. Kidney pathophysiology: key features that need to be represented in animal models
Diabetic nephropathy is a progressive complication of DM, a leading cause of end-stage renal failure globally. A main clinical feature that presents in both Type1 and Type2 diabetic patients is albuminuria where the first manifestation typically occurs as microalbuminuria, defined as albumin excretion of 30-299mg in 24 hours. Over time, microalbuminuria progresses to proteinuria, defined as albumin excretion of over 500mg in 24 hours leading to overt diabetic nephropathy[104]. Hyperglycaemia acts as the major driving force of the progression to diabetic nephropathy with the generation of ROS, formation of AGEs, and the activation of polyol and PKC pathways all contributing to glomerular damage. The downstream consequences include inflammation, thickening of the glomerular basement membrane and microaneurysm formation[105]. In addition, accumulation of extracellular matrix proteins such as collagens and fibronectin replaces healthy renal architecture, leading to mesangial expansion and reduction of filtration surface area, which in turn is further disrupted by the thickening of glomerular basement membranes[106].