From the periphery of the glomerular capillary wall toward the center of disease - Podocyte injury comes of age in diabetic nephropathy

被引:496
作者
Wolf, G
Chen, SD
Ziyadeh, FN
机构
[1] Univ Penn, Penn Ctr ol Studies Kidney Dis, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA
[2] Univ Hosp, Innere Med Klin 3, Dept Internal Med, Jena, Germany
关键词
D O I
10.2337/diabetes.54.6.1626
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta 1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.
引用
收藏
页码:1626 / 1634
页数:9
相关论文
共 111 条
[1]   Transforming growth factor-β1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins -: A central pathway in progressive glomerulosclerosis [J].
Abbate, M ;
Zoja, C ;
Morigi, M ;
Rottoli, D ;
Angioletti, S ;
Tomasoni, S ;
Zanchi, C ;
Longaretti, L ;
Donadelli, R ;
Remuzzi, G .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 161 (06) :2179-2193
[2]  
ADLER S, 1994, J AM SOC NEPHROL, V5, P1165
[3]  
ADLER S, 1992, AM J PATHOL, V141, P571
[4]   Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy [J].
Benigni, A ;
Gagliardini, E ;
Tomasoni, S ;
Abbate, M ;
Ruggenenti, P ;
Kalluri, R ;
Remuzzi, G .
KIDNEY INTERNATIONAL, 2004, 65 (06) :2193-2200
[5]   Add-on anti-TGF-β antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat [J].
Benigni, A ;
Zoja, C ;
Corna, D ;
Zatelli, C ;
Conti, S ;
Campana, M ;
Gagliardini, E ;
Rottoli, D ;
Zanchi, C ;
Abbate, M ;
Ledbetter, S ;
Remuzzi, G .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (07) :1816-1824
[6]   Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM [J].
Berg, UB ;
Torbjörnsdotter, TB ;
Jaremko, G ;
Thalme, B .
DIABETOLOGIA, 1998, 41 (09) :1047-1056
[7]  
Bonnet F, 2001, DIABETOLOGIA, V44, P874
[8]   Angiotensin II type 1-receptor mediated changes in heparan sulfate proteoglycans in human SV40 transformed podocytes [J].
Brinkkoetter, PT ;
Holtgrefe, S ;
Van Der Woude, FJ ;
Yard, BA .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2004, 15 (01) :33-40
[9]   Biochemistry and molecular cell biology of diabetic complications [J].
Brownlee, M .
NATURE, 2001, 414 (6865) :813-820
[10]   Altering expression of α3β1 integrin on podocytes of human and rats with diabetes [J].
Chen, HC ;
Chen, CA ;
Guh, JY ;
Chang, JM ;
Shin, SJ ;
Lai, YH .
LIFE SCIENCES, 2000, 67 (19) :2345-2353