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From Fibrosis to Sclerosis

Mechanisms of Glomerulosclerosis in Diabetic Nephropathy

¹ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
² Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan
³ Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan

Corresponding author: Frank C. Brosius, University of Michigan, 5520 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0680. E-mail: fbrosius@umich.edu

Abbreviations: APC, activated protein C; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal–related kinase; JAK, Janus kinase; STAT, signal transducers and activation of transcription; TGF, transforming growth factor; VEGF, vascular endothelial growth factor

The first 300 words of the full text of this article appear below.

Progression of diabetic nephropathy to end-stage kidney disease is mediated by a host of processes, but none is as important as the gradual, inexorable scarring of the renal glomerulus, known as glomerulosclerosis. Hence, a host of studies over the decades have attempted to elucidate the molecular mechanisms that lead to this chronic sclerosing condition so that effective therapies and preventative strategies can be developed. Over the past several years, the general understanding of the pathogenic factors that lead to this important feature of diabetic nephropathy has improved considerably. Glomerulosclerosis in diabetic nephropathy is caused by accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space, resulting in fibrosis manifested by either diffuse or nodular changes (1). The most common matrix proteins detected are collagen types I, III, and IV and fibronectin (2). These accumulate both due to increased synthesis by mesangial cells and reduced degradation by mesangial matrix metalloproteinases (3). Over 20 years ago, Mauer et al. (4) established the clear link between mesangial matrix expansion and progression of diabetic kidney disease by demonstrating that measures of mesangial expansion strongly predicted the clinical manifestations of diabetic nephropathy. Since then, the critical charge to investigators has been to elucidate the mechanisms that promote glomerulosclerosis in diabetic nephropathy. In this brief perspective, we will review pathogenic processes that appear to be critical in the development of diabetic glomerulosclerosis, emphasizing newer findings and insights.

	CLASSICAL VIEW OF DIABETIC GLOMERULOSCLEROSIS

 
During the 1990s, a general consensus emerged about major signaling mechanisms involved in stimulating mesangial cell synthesis of ECM proteins (Fig. 1). In this consensus view, high extracellular glucose induces an increase in glucose uptake via increased expression of the facilitative glucose transporter GLUT1 (5,6). The resultant enhancement in glucose metabolic flux leads to . . . [Full Text of this Article]

	ALL GLOMERULAR CELL TYPES ARE INVOLVED IN DIABETIC GLOMERULOSCLEROSIS

 

	NEWER OBSERVATIONS ON MECHANISMS OF DIABETIC GLOMERULOSCLEROSIS

 
1. Systemic and paracrine: inflammation.
2. Systemic and mesangial cell: bradykinin 2 receptor blockade.
3. Paracrine and mesangial cell: lipids and lipid mediators.
4. Mesangial cell: microRNA regulation of TGF-β signaling.
5. Mesangial cell: Janus kinase/signal transducer and activation of transcription pathway activation.
6. Endothelial cell/podocyte: reduction in endothelial nitric oxide synthase and vascular endothelial growth factor.
7. Endothelial cell/podocyte and paracrine: reduction of activated protein C.

	CONCLUSIONS

 

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