What is diabetic nephropathy?

Diabetic nephropathy is a serious complication of diabetes mellitus characterized by damage to the kidneys’ filtering units, known as nephrons. It is one of the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. Diabetic nephropathy develops gradually over time, usually taking many years to manifest significant symptoms.


The condition typically occurs in individuals with either type 1 or type 2 diabetes, although it is more common and tends to progress more rapidly in those with type 1 diabetes. The primary risk factors for developing diabetic nephropathy include poor glycemic control (high blood sugar levels over an extended period), hypertension (high blood pressure), and genetic predisposition.


The pathogenesis of diabetic nephropathy involves multiple complex mechanisms, including:

  • Glomerular Injury: High blood glucose levels can damage the delicate blood vessels (glomeruli) within the kidneys, leading to a condition called glomerulosclerosis. Glomerulosclerosis involves thickening and scarring of the glomerular basement membrane, impairing the kidneys’ ability to filter waste products and excess fluids from the blood.


  • Increased Renal Blood Flow and Pressure: Diabetes can cause abnormalities in the regulation of renal blood flow and pressure, leading to increased blood flow and pressure within the glomeruli. This can further damage the glomeruli and exacerbate protein leakage into the urine (proteinuria).


  • Inflammation and Oxidative Stress: Chronic inflammation and oxidative stress play significant roles in the development and progression of diabetic nephropathy. Elevated levels of pro-inflammatory cytokines and reactive oxygen species (ROS) contribute to kidney tissue damage and dysfunction.


  • Renin-Angiotensin-Aldosterone System (RAAS) Activation: Diabetes can lead to dysregulation of the RAAS, a hormonal system that helps regulate blood pressure and fluid balance. Activation of the RAAS can promote kidney injury and fibrosis, contributing to the progression of diabetic nephropathy.


  • Podocyte Dysfunction: Podocytes are specialized cells in the glomeruli that help maintain the integrity of the filtration barrier. Dysfunction of podocytes can occur in diabetic nephropathy, leading to increased protein leakage into the urine and progressive kidney damage.


What is the relationship between diabetic nephropathy and oxidative stress?

The relationship between diabetic nephropathy and oxidative stress is well-established and plays a significant role in the pathogenesis and progression of the disease. Oxidative stress occurs when there’s an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to neutralize them with antioxidants. Several factors contribute to oxidative stress in diabetic nephropathy:


  • Hyperglycemia: Chronic hyperglycemia (high blood sugar levels) is a key driver of oxidative stress in diabetes. Elevated glucose levels lead to increased production of ROS through various pathways, including glucose auto-oxidation, advanced glycation end products (AGEs) formation, and activation of protein kinase C (PKC) and the hexosamine pathway. Excessive ROS production damages cellular components, such as lipids, proteins, and DNA, contributing to kidney tissue injury and dysfunction.


  • Inflammation: Chronic low-grade inflammation is a hallmark of diabetic nephropathy and contributes to oxidative stress. Inflammatory mediators, such as cytokines and chemokines, activate immune cells and stimulate the production of ROS as part of the immune response. In turn, ROS can further activate inflammatory signaling pathways, creating a positive feedback loop that exacerbates tissue damage and inflammation in the kidneys.


  • Renin-Angiotensin-Aldosterone System (RAAS) Activation: Dysregulation of the RAAS, a hormonal system that helps regulate blood pressure and fluid balance, is common in diabetic nephropathy. Activation of the RAAS promotes oxidative stress through several mechanisms, including stimulation of NADPH oxidase activity, increased production of ROS, and impaired antioxidant defenses. ROS generated by the RAAS contribute to kidney injury and fibrosis, accelerating the progression of diabetic nephropathy.


  • Mitochondrial Dysfunction: Mitochondria are a major source of ROS production in cells and play a crucial role in cellular energy metabolism. Dysfunction of mitochondria, such as impaired electron transport chain function or reduced antioxidant defenses, can lead to increased ROS generation and oxidative stress. Mitochondrial dysfunction is implicated in the pathogenesis of diabetic nephropathy and contributes to kidney tissue injury and dysfunction.


  • Antioxidant Defenses: In diabetic nephropathy, there is often a depletion of endogenous antioxidant defenses, such as superoxide dismutase (SOD), catalase, glutathione peroxidase, and reduced glutathione (GSH). Decreased antioxidant capacity leaves the kidneys more vulnerable to oxidative damage and exacerbates tissue injury.


Overall, oxidative stress is a central mechanism underlying the development and progression of diabetic nephropathy.