Diabetic nephropathy represents a major cause of morbidity and mortality in patients with diabetes. Identification of the pathophysiological pathways that lead to adverse renal events and the development of novel agents that target these pathways are essential to prevent the rising incidence of diabetic nephropathy and improve patient outcomes. This Focus issue provides an update of the mechanisms that are believed to have key roles in the pathogenesis of diabetic nephropathy and the strategies that might be able to manipulate these pathways in such a way as to prevent or treat this disease.


Aggressively preventing diabetes

Robert W. Schrier


Nature Reviews Nephrology 6, 313 (2010)


The RAAS in the pathogenesis and treatment of diabetic nephropathy

Piero Ruggenenti, Paolo Cravedi & Giuseppe Remuzzi


Nature Reviews Nephrology 6, 319-330 (2010)

Angiotensin II and other components of the renin–angiotensin–aldosterone system (RAAS) have a central role in the pathogenesis and progression of diabetic renal disease. In this Review, Ruggenenti and colleagues describe the roles of angiotensin II and other effectors of the RAAS—such as aldosterone and renin—in the pathogenesis and progression of diabetic renal disease. In addition, they discuss the renoprotective and cardioprotective effects that inhibition of these effectors may have in individuals with diabetes.

Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms

Stephen Tonna, Assam El-Osta, Mark E. Cooper & Chris Tikellis


Nature Reviews Nephrology 6, 332-341 (2010)

Chronic hyperglycemia is associated with the presence and evolution of diabetic complications in type 1 and type 2 diabetes. Intensive glycemic control can have beneficial effects on such complications, particularly diabetic nephropathy. This Review discusses the phenomenon of 'metabolic memory', in which the beneficial effects of intensive glycemic control persist after a return to more usual (often worse) glycemic control. This phenomenon is not well understood, but preliminary studies indicate that biochemical mechanisms such as advanced glycation and molecular pathways involving epigenetic events might have a role.

Nuclear hormone receptors in diabetic nephropathy

Xiaoxin X. Wang, Tao Jiang & Moshe Levi


Nature Reviews Nephrology 6, 342-351 (2010)

Nuclear hormone receptors are transcription factors that regulate multiple biological pathways and may provide protection against metabolic, inflammatory and cardiovascular diseases. In this Review, Wang and colleagues discuss the evidence that supports a role for nuclear hormone receptors in the pathogenesis of diabetic nephropathy and describe how the manipulation of these receptors may provide new avenues for the treatment of this disease.

RAGE and the pathogenesis of chronic kidney disease

Vivette D'Agati & Ann Marie Schmidt


Nature Reviews Nephrology 6, 352-360 (2010)

The receptor for advanced glycation endproducts (RAGE) was first identified as a signal transduction receptor for the advanced glycation endproducts (AGEs) of proteins and lipids. Experiments using transgenic mouse models, pharmacological blockade of RAGE and genetic modification or deletion of RAGE indicate a key role for RAGE in the pathogenesis of various nephropathies including diabetic nephropathy. In this Review, D'Agati and Schmidt discuss the evidence linking RAGE to diabetic nephropathy and chronic kidney disease.

Role of triglyceride-rich lipoproteins in diabetic nephropathy

John C. Rutledge, Kit F. Ng, Hnin H. Aung & Dennis W. Wilson


Nature Reviews Nephrology 6, 361-370 (2010)

A large body of evidence suggests that excess amounts of lipoproteins and lipids can induce glomerular injury and tubulointerstitial fibrosis, and may accelerate the progression of nephropathy in patients with diabetes. In this Review, John Rutledge and colleagues describe the influence of lipoproteins, specifically triglyceride-rich lipoproteins, on the development and perpetuation of diabetic nephropathy.

New pharmacological treatments for improving renal outcomes in diabetes

Anne-Emilie Declèves & Kumar Sharma


Nature Reviews Nephrology 6, 371-380 (2010)

Improved understanding of the pathogenesis of fibrosis associated with diabetic kidney disease has led to the identification of several novel targets for treatment. In this Review, Declèves and Sharma discuss the clinical and experimental evidence supporting various novel pharmacological approaches aimed at controlling the progression of diabetic nephropathy. The potential therapeutic agents discussed include direct renin inhibitors, statins, and antifibrotic drugs.


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