Diabetic Nephropathy and Oxidative Stress
Diabetic Nephropathy and Oxidative Stress
US Endocrine Disease 2006 - June 2006
Published: October 2008
Published: October 2008
Diabetic kidney disease is rapidly becoming the major cause of end-stage renal disease in the US and the number of patients with diabetic kidney disease is increasing at an epidemic rate worldwide. It is widely accepted that the principal cause of all diabetic complications is increased blood sugar. Although this sounds like an obvious statement, it actually wasn’t until the Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients,1 published in the early 1990s, and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients,2 published in the late 1990s, that definitive proof was published that as blood sugar control improved, there was a continuous decrease in the development and progression of diabetic complications.
Thus, it would seem that tight control of blood sugar could end the scourge of diabetic complications.A pancreas transplant (and, in the future, possibly islet cell transplants) is the only way to perfectly control blood sugar. All other available methods for controlling blood sugar, including oral hypoglycemic drugs, periodic insulin shots, and continuous insulin pumps, still allow for modest elevations of blood sugar out of the normal range.These repeated fluctuations in blood sugar that occur throughout the day in diabetic patients are enough to cause cell damage. That is to say, one does not need persistent high blood sugars to cause damage but rather repeated excursions out of the normal range are enough to activate damaging cellular events and to impair critical cellular defense processes. Until there is a cure for diabetes, it is necessary to understand the deleterious mechanisms effected by increased glucose in order to prevent complications.
Pathophysiologic Mechanisms Associated with Diabetic Kidney Disease
The following mechanisms have been shown to play a role in the development and progression of diabetic kidney disease:
- Activation of protein kinase Cβ (PKCβ)3—this is a serine/threonine kinase that has multiple actions on cellular functions leading to cell damage.
- Increased advanced glycation end products (AGEs)4—these are produced by the prolonged exposure of amino acids to increased glucose levels. The AGEs cause cellular damage by altering cell protein actions and cell membrane functions.
- Increased transforming growth factor β (TGFβ)5— this protein leads to activation of a number of inflammatory compounds leading to fibrosis in the kidney.
- Hypertension and hyperfiltration in the glomerulus (which is the filtering unit of the kidney—there are about 1 million in each kidney)5—the increased pressure in the glomerulus is decreased by blocking the actions of angiotensin II.
- Increased aldose reductase which produces sorbitol.
- Others.
References:
- The Diabetes Control and Complications Trial Research Group,“The effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-dependent diabetes mellitus”, N Engl J Med (1993);329: pp. 977–986.
- UK Prospective Diabetes Study (UKPDS) Group,“Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)”, Lancet (1998);352:
pp. 837–853.
- Tuttle K R,Anderson P W,“A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta
inhibition”, Am J Kidney Dis (2003);42: pp. 456–465.
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(2005);12: pp. 212–222.
- Schena F P, Gesualdo L, “Pathogenetic mechanisms of diabetic nephropathy”, J Am Soc Nephrol (2005);16(Suppl 1):
pp. S30–S33.
- Lee H,Yu M-R,Yang Y, Jiang Z, Hunjoo H, “Reactive oxygen species-regulated signaling pathways in diabetic nephropathy”, J
Am Soc Nephrol (2003);14: pp. S221–S226.
- Koya D, Hayashi K, Kitada M et al.,“Effects of antioxidants in the diabetes-induced oxidative stress in the glomeruli of diabetic
rats”, J Am Soc Nephrol (2003);14: pp. S250–S253.
- Beisswenger P J, Drummond K S, Nelson R G et al.,“Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative
stress”, Diabetes (2005);54: pp. 3,274–3,281.
- Brune B, Zhou J, von Knethen A,“Oxidative stress and NO”, Kidney International (2003);63: pp. S22–S24.
- Brownlee M,“Biochemistry and molecular cell biology of diabetic complicatioins”, Nature (2001);414: pp. 813–820.
- Xu Y, Osborne B W, Stanton R C,“Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of protein kinase A which contributes to oxidative stress in rat kidney cortex”, Am J Physiol (Renal Physiol) (2005);289: pp. F1,040–F1,047.
- Ceriello A, Morocutti A, Mercuri F et al.,“Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy”, Diabetes (2000);49: pp. 2,170–2,177.
- DeRubertis F R, Craven P A, Melhem M F, Salah E M,“Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction”, Diabetes (2004);53: pp. 762–768.
