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.