Unlocking Diabetic Nephropathy through its key pathological mechanisms - Oxidative Stress and Fibrosis
Global burden of Diabetic Nephropathy
Kidney disease associated with diabetes, Diabetic Nephropathy (DN), is a leading cause of End-Stage Renal Failure and a strong predictor of mortality (1) . Recent advances in our understanding of the pathologic processes underlying renal dysfunction and damage have revealed an array of new markers to assist in the early detection of the disease, especially in diabetic patients with normal urinary albumin levels (normoalbuminuria).
Key Pathologic Processes - Oxidative Stress and Fibrosis
The pathophysiology of DN is complex and multifactorial, involving metabolic and haemodynamic alterations, oxidative stress, chronic inflammation and activation of the renin-angiotensin system. These insults induce early endothelial cell dysfunction and podocyte injury followed by extracellular matrix (ECM) deposition at the glomerular basement membrane (GBM) and mesangium, which is assessed histologically as GBM thickening, mesangial expansion and glomerulosclerosis. Concomitant infiltration and activation of immune cells further promotes renal inflammation, oxidative stress and damage. Progressive fibrosis in the glomerular and tubular (interstitial) compartments is a hallmark feature of advanced DN (2).
Microalbuminuria, that is the excretion of 30–300 mg of albumin over 24 hours, is an important biomarker currently used in the diagnosis of DN. Identification of novel, disease-specific biomarkers (see table below) presents immense value for kidney disease research, drug discovery and patient care. Leading the field are markers of oxidative stress and fibrosis.
Uncontrolled production of Reactive Oxygen Species (ROS) and their associated damage products- such as lipid peroxides - have been shown to play a central role in both early glomerular and subsequent tubular changes in DN (3). Agents targeting renal oxidative stress- by blocking enzymatic production or bolstering antioxidant defenses- have demonstrated anti-inflammatory and anti-fibrotic effects, and represent an active area of investigation (4,5).
Pathological accumulation of matrix proteins- including collagen IV and fibronectin - in the glomerulus and tubulointerstitial space is significantly associated with renal outcomes in diabetic patients (6,7). Urinary type IV collagen excretion is significantly elevated in diabetes and correlates closely with renal dysfunction (8). Interestingly, new anti-diabetic therapies have shown protective affects against renal fibrosis in a mouse model of type 2 diabetes, including reduction in glomerular collagen IV (9).
The future of Precision Medicine in global healthcare and drug development depends on the selection and validation of rapid, reliable, and quantitative assays of disease biomarkers (10).
Cobo Scientific has carefully selected 28 potential Biomarker Assays (ELISA) to support the global DN research field. Search directly below for your biomarker of interest.
Oxidative Stress | Fibrosis | Inflammation | Injury and Dysfunction
Transforming growth factor β (TGF-β1)
Matrix metalloproteinase-2 (MMP-2)
Soluble TNF receptors (sTNFR)-1
Soluble TNF receptors (sTNFR)-2
Fibroblast growth factor (FGF)-21
Fibroblast growth factor (FGF)-23
Adipocyte-fatty acid binding protein (A-FABP)
Monocyte chemotactic protein-1 (MCP-1)
Tumor necrosis factor alpha (TNFα)
Injury and Dysfunction
Kidney injury molecule-1 (KIM-1)
Neutrophil gelatinase-associated lipocalin (NGAL)
Liver-type fatty acid binding protein (L-FABP)
1. Van der Velde, M. et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int. 79(12):1341-52 (2011)
2. Tervaert, TW. et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 21(4): 556-63 (2010)
3. Di Marco, E. et al. Are reactive oxygen species still the basis for diabetic complications? Clin Sci. 129(2):199-216 (2015)
4. He, T. et al. Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway. J Mol Med. 94(12):1359-1371 (2016)
5. Jha, JC. Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy. J Am Soc Nephrol. 25(6):1237-54 (2014)
6. Okonogi, H. et al. Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus. Clin Nephrol. 55(5):357-64 (2001)
7. An, Y. et al. Renal histologic changes and the outcome in patients with diabetic nephropathy. Nephrol Dial Transplant. 30(2):257-66 (2015)
8. Cohen, MP. et al. Serum type IV collagen in diabetic patients at risk for nephropathy. Diabetes Care. 24(8):1324-7 (2001)
9. Gallo, LA. et al. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice. Sci Rep. 26;6:26428 (2016).
10. Lyman, GH and Moses, HL. Biomarker Tests for Molecularly Targeted Therapies--The Key to Unlocking Precision Medicine. N Engl J Med. 375(1):4-6 (2016).
© CoboSci Press 2017. All rights reserved.
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Diabetic Nephropathy - BioMarker Overview
Download the BioMarker Overview Table here, including detailed information about 28 suggested biomarker assays.
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