Abstract
Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure.
Highlights
Diabetes is a group of chronic metabolic diseases marked by high plasma glucose levels (usually fasting plasma glucose (FPG) is ≥126 mg/dL) resulting from defects in insulin secretion or insulin action or both
Before we review diabetes-induced pathological changes of glomerulus in detail, we will give an account on the contributory role of glomerular filtration barrier in fluid filtration and protein retention underscoring their structural and functional features
Patients having diabetes are more likely to develop microalbuminuria that is used as a marker for abnormal renal function
Summary
Diabetes is a group of chronic metabolic diseases marked by high plasma glucose levels (usually fasting plasma glucose (FPG) is ≥126 mg/dL) resulting from defects in insulin secretion or insulin action or both. In line with the increasing incidence of diabetes, cases of chronic kidney disease (CKD) or end-stage renal damage (ESRD) have been growing significantly, since CKD is directly related to diabetes and/or hypertension. Diabetes-mediated chronic hyperglycemia evokes the onset and progression of renal injury because of its role in causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. It is noted that GFB consists of three layers, where the visceral epithelial cells (podocytes) layer is highly vulnerable to ROS because of its nonproliferative nature even in response to injury [6, 7] This results in early podocyte loss at the onset of diabetes and initiates increased protein excretion in urine. Renal tubules rather increasingly contribute to the development of advanced stage of kidney damage which is beyond the scope of this review
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