Unlocking Diabetic Nephropathy (DN) through its key pathological mechanisms - Oxidative Stress and Fibrosis https://coboscientific.com/biomarkers/diabetic-nephropathy/

1. 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 mortality1
. 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 DN2
.
Emerging biomarkers
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 1, below) presents immense value for kidney
disease research, drug discovery and patient care. Leading the field are markers of
oxidative stress and fibrosis.
Oxidative stress
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 DN3
. 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
investigation4,5
.
Fibrosis
Pathological accumulation of matrix proteins- including collagen IV and fibronectin - in
the glomerulus and tubulointerstitial space is significantly associated with renal outcomes
in diabetic patients6,7
. Urinary type IV collagen excretion is significantly elevated in
diabetes and correlates closely with renal dysfunction8
. Interestingly, new anti-diabetic

2. therapies have shown protective affects against renal fibrosis in a mouse model of type 2
diabetes, including reduction in glomerular collagen IV9
.
Table 1: Summary of potentially useful biomarkers of DN
Disease process Marker
Fibrosis Collagen IV
Fibronectin
Transforming Growth Factor β (TGF-β1)
Matrix MetalloProteinase-2 (MMP-2)
Tissue Inhibitor of MetalloProtease-1 (TIMP-1)
Oxidative stress Lipid peroxidation
MalonDiAldehyde (MDA)
8-Oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG)
Superoxide Dismutase (SOD)
Inflammation Soluble TNF receptors-1 (sTNFR-1)
Soluble TNF receptors-1 (sTNFR-2)
Fibroblast Growth Factor-21 (FGF-21)
Fibroblast Growth Factor-23 (FGF-23)
Adipocyte-Fatty Acid Binding Protein (A-FABP)
Monocyte Chemotactic Protein-1 (MCP-1)
Tumor Necrosis Factor alpha (TNFα)
Interleukin-6 (IL-6)
Interleukin-8 (IL-8)
Interleukin-18 (IL-18)
Injury and dysfunction Cystatin C (serum)
Kidney Injury Molecule-1 (KIM-1)
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
Liver-type Fatty Acid Binding Protein (L-FABP)
N-Acetyl-beta-Glucosaminidase (NAG)
Nephrin
PodoCalyXin (PCX)
Immunoglobulin G (IgG)
Alpha 1-Microglobulin (A1M)
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
biomarkers10
. We hope that the above selection of potential biomarker assays will further
contribute to the ongoing disease research within the Diabetic Nephropathy field.
References
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. 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).
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