EDITORIALS Molecular Mechanisms of Diabetic Mesangial Cell Hypertrophy: A Proliferation of Novel Factors GUNTER WOLF Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Hamburg, Germany. The French clinician Pierre-Francois-Olivier Rayer (1793–1867) wrote more than 150 years ago: “In diabetes, one finds hypertro- phy of the renal cortex...the vessels are enlarged and the Mal- phigian corpuscles are much more prominent” (1). The underly- ing mechanisms of this correct description of diabetic glomerular hypertrophy, based exclusively on macroscopic studies, have puz- zled and challenged nephrophiles ever since. Extensive morpho- metric studies on renal specimens from patients with diabetes mellitus type 1, performed almost thirty years ago, provided convincing evidence that glomerular, mainly mesangial cell, hy- pertrophy and basement membrane thickening are among the earliest pathologic alterations found in diabetic nephropathy (2,3). However, the issue is not a simple one and requires a meaningful definition of cellular hypertrophy and tools to measure it. Mesan- gial expansion associated with early diabetic nephropathy is cer- tainly a combination of increased deposition of extracellular ma- trix components and stimulation of mesangial cell growth (4). Cell culture studies and an enormous deluge of novel information regarding cell cycle regulation in the last decade have provided important insights into mechanisms of mesangial cell hypertrophy on a molecular level (5). An organ can increase in overall size due to an increase in cell number caused by stimulated proliferation or decreased apoptosis or an increase in individual cell size called hyper- trophy (5). Cell hypertrophy could be defined as cell enlarge- ment due to an increase in RNA and protein content without concomitant changes in DNA synthesis (4). This definition includes active changes in cellular metabolism and growth regulation, indicating that hypertrophy is more than passive cell swelling. Hypertrophy could be cell cycle– dependent or cell cycle–independent (5). Cell cycle independent hypertro- phy may be caused by reduced protein degradation due to an inhibition of various proteases (6). The concept that mesangial cell hypertrophy is rather an active cell cycle– dependent pro- cess comes from studies in which murine mesangial cells were exposed to high D-glucose concentrations (7). Raising the medium glucose concentrations from 100 to 450 mg/dl has a biphasic effect on cell proliferation. It stimulates an early limited proliferation after 24 h (7). However, prolonged expo- sure to high glucose inhibits mesangial cell proliferation and induces hypertrophy (7). A similar biphasic growth response of mesangial cells has also been observed in experimentally in- duced diabetes in vivo (8). Cell cycle analysis revealed that prolonged incubation in high glucose arrests cells in the G 1 - phase of the cell cycle (7). This G 1 -phase arrest is partly mediated by autocrine synthesis and activation of transforming growth factor– (TGF-) (7). In exploring potential molecular mechanisms of this cell cycle arrest, it was discovered that high glucose induces ,partly but not exclusively through TGF-, expression of p21 Cip1 and p27 Kip1 , two cyclin-dependent ki- nase (CDK) inhibitors (9,10). These CDK inhibitors bind to cyclin/CDK complexes, inhibit their activity, and thereby pre- vent G 1 /S-phase transit (5). Recent evidence indicates that high glucose activates MAP kinases, which in turn directly phos- phorylate p27 Kip1 on serine residues and prolong the half-life of this CDK inhibitor (11). In contrast, high glucose directly stimulates transcription of p21 Cip1 (12). Mesangial cell expres- sion of p21 Cip1 and p27 Kip1 also occurs in different models of type 1 and 2 diabetes in vivo and could be modulated by angiotensin-converting enzyme (ACE) inhibitor treatment (12,13). The functional role of p27 Kip1 in mediating hypertro- phy emanates from studies using p27 Kip1 knockout (-/-) mesangial cells (14). In contrast to p27 Kip1 +/+ mesangial cells, high glucose fails to induce hypertrophy in p27 Kip1 -/- mesangial cells. However, reconstituting p27 Kip1 expression in p27 Kip1 -/- cells with an inducible vector system restores the hypertrophic phenotype induced by high glucose (14). These results clearly demonstrate that p27 Kip1 is required for glucose- induced cell cycle arrest and hypertrophy. In their article published in this issue of JASN, Wahab et al. (15) bring a new twist to this complex story by demonstrating that connective tissue growth factor (CTGF) mediates mesan- gial cell hypertrophy, presumably by induction of CDK inhib- itors. CTGF was originally isolated from human umbilical vein endothelial cells in a search for peptides related to platelet- derived growth factor (16). It is a cysteine-rich peptide con- taining 349 amino acids and belongs to a family of growth factors called CNN (members include cef10, nov, wisp-1) that share certain conserved domains (17). CTGF is produced by a wide variety of different cells, including fibroblasts, endothe- lial cells, chondrocytes, and smooth muscle cells (18). In the kidney, CTGF is expressed in glomerular endothelial, mesan- gial, and tubular cells (18). Early data using fibroblasts indicate that TGF-1 is a strong inducer of CTGF, and the CTGF Correspondence to Dr. Gunter Wolf, Department of Medicine, Division of Ne- phrology and Osteology, University of Hamburg, University Hospital Eppendorf, Pavilion 26, Martinistr. 52, D-20246 Hamburg, Germany. Phone: 49-40-42803- 5011; Fax: 49-40-42803-5186; E-mail: Wolf@uke.uni-hamburg.de 1046-6673/1310-2611 Journal of the American Society of Nephrology Copyright © 2002 by the American Society of Nephrology J Am Soc Nephrol 13: 2611–2613, 2002