Diabetic nephropathy has severe individual and societal consequences, owing to its high morbidity, mortality and health-care costs
Despite the availability of anti-glycaemic, renoprotective and antihypertensive agents, diabetes mellitus remains the most common cause of end-stage renal disease in developed countries
New biomarkers that can identify patients at risk of diabetic nephropathy are needed, as well as new agents that directly target the pathogenic pathways of diabetic nephropathy
Growing evidence suggests that the complement system has a pathogenic role in the development of diabetic nephropathy
Mannose-binding protein is a strong biomarker of diabetic nephropathy in patients with type 1 diabetes mellitus (T1DM) and T2DM; H-ficolin might be useful to identify patients with T1DM at risk of persistent microalbuminuria
Inhibiting specific components of the complement system might be an effective therapeutic strategy to treat diabetic nephropathy
The development of type 1 and type 2 diabetes mellitus has a substantial negative impact on morbidity and mortality and is responsible for substantial individual and socioeconomic costs worldwide. One of the most serious consequences of diabetes mellitus is the development of diabetic angiopathy, which manifests clinically as microvascular and macrovascular complications. One microvascular complication, diabetic nephropathy, is the most common cause of end-stage renal disease in developed countries. Although several available therapeutic interventions can delay the onset and progression of diabetic nephropathy, morbidity associated with this disease remains high and new therapeutic approaches are needed. In addition, not all patients with diabetes mellitus will develop diabetic nephropathy and thus new biomarkers are needed to identify individuals who will develop this life-threatening disease. An increasing body of evidence points toward a role of the complement system in the pathogenesis of diabetic nephropathy. For example, circulating levels of mannose-binding lectin (MBL), a pattern recognition molecule of the innate immune system, have emerged as a robust biomarker for the development and progression of this disease, and evidence suggests that MBL, H-ficolin, complement component C3 and the membrane attack complex might contribute to renal injury in the hyperglycaemic mileu. New approaches to modulate the complement system might lead to the development of new agents to prevent or slow the progression of diabetic nephropathy.
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The author declares no competing financial interests.
- Polyol pathway
A pathway whereby aldoketo-reductase enzymes use nicotinic acid adenine dinucleotide phosphate (NADPH) to reduce sugar-derived carbonyl compounds to their respective sugar alcohols (polyols). Glucose is converted to sorbitol, and galactose to galactitol. Further, sorbitol is oxidized to fructose by sorbitol dehydrogenase, with a reduction of NAD+ to NADH. The rate-limiting step of the polyol pathway is regulated by aldose reductase.
- Hexosamine pathway
A pathway whereby glucosamine-6-phosphate is made from fructose-6-phosphate and an amino group from glutamine, and glucosamine-6-phosphate is acetylated through an exchange with acetyl-coenzyme A to form N-acetylglucosamine- 6-phosphate. The 6-phosphate forms N-acetyl-glucosamine-1-phosphate through the action of an isomerase. Finally, through a reaction with uridine triphosphate, uridine diphosphate-N-acetylglucosamine is formed.
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Flyvbjerg, A. The role of the complement system in diabetic nephropathy. Nat Rev Nephrol 13, 311–318 (2017). https://doi.org/10.1038/nrneph.2017.31