Involvement of PAR’s in progression of diabetic kidney disease
Diabetic kidney disease is one of the most common complications in patients suffering from diabetes mellitus which may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD) [3,12,46]. Initially, in nephropathic conditions hyperglycemia leads to renal hemodynamic changes including abnormal substrate delivery (glucose, free fatty acid) for energy production in the mitochondria [2, 11, 47]. There is also an overproduction of electron donors NADPH and FADH2 which disturbs the electron transport chain in the mitochondria. As a result of mitochondrial dysfunction, there is increased reactive oxygen species (ROS) production which promotes oxidative stress resulting in podocyte and renal tubular cell apoptosis [46-48]. Moreover, hyperglycemic stress increases the production of inflammatory cytokines (TNF-α, IL-6) resulting in glomerular changes including an increased proliferation of mesangial cells. The diabetic condition also results in afferent vasodilation and hyperaminoacidemia which promotes glomerular hyperfiltration and hyperperfusion. However, the high production of angiotensin-II at the efferent arteriole leads to vasoconstriction [5, 48, 49]. Notably, consistent vasoconstriction of efferent arteriole produces effacement of podocyte foot processes due to increased intraglomerular pressure and induces destruction of the glomerular filtration barrier which further leads to albuminuria [5, 49]. Evidence from earlier studies has suggested that both type-1 and type-2 diabetes conditions up-regulate thrombin generation [38]. Since thrombin is a PAR1 activator as mentioned above thus it is possible that PAR1 activation might play a key role in the development of glomerular injury in diabetic kidneys.