Gunter Wolf
Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Hamburg, Germany
Address All Correspondence To:
The number of patients suffering from end-stage renal disease (ESRD) is continuously growing with prevalence rates of approximately 400 per million in Europe and 975 in the United States, respectively (1). Furthermore, a current shortage in kidneys for transplantation as well as chronic allograft rejection may also influence the overall number of patients on dialysis. Although the quality of dialysis treatment has markedly improved in the last decades, patients with ESRD undergoing maintenance dialysis have still a considerable high morbidity and mortality (2). Besides the non-countable human cost regarding suffering of these patients, the financial cost of caring is enormous, particular in the face of dwindling economical health resources. Therefore, the development of therapeutic strategies to prevent, or at least, to slow the progression of chronic renal disease is essential (3).
Role of ANG II in the progression of renal diseases
Several recent studies have provided clear evidence that angiotensin-converting enzyme (ACE)-inhibitors slow the progression of renal disease (4,5). These effects are due to a reduction in angiotensin II (ANG II) formation, and are mainly independent from a concomitant reduction in systemic blood pressure (4,5). ANG II has many diverse effects on the kidney. Although a reduction in proteinuria and normalization of glomerular hemodynamics may clearly contribute to these beneficial effects of ACE-inhibitor treatment (5), a recent deluge of experimental data suggests that ANG II exerts non-hemodynamic actions on the kidney which may be all involved in the progression of renal disease. These non-hemodynamic effects of ANG II and their role in the progression of renal disease have been recently reviewed in detail (6-8), and only some major key points will be described here.
Animal experiments have provided evidence that proliferation of glomerular cells as well as tubular hypertrophy is an early sign of compensatory mechanisms after injury that may be finally develop into a maladaptive response characterized by glomerular sclerosis and tubulointerstitial fibrosis (9). In this regard, ANG II stimulates glomerular and tubular growth as well as the synthesis of extracellular matrix proteins (7,8,10). In cell culture, ANG II stimulates the proliferation of glomerular endothelial and mesangial cells (10,11).
In addition, the peptide also increases the biosynthesis of type I collagen in mesangial cells, an effect depending on an increase in transcription (10). In contrast, ANG II induces hypertrophy of cultured tubular cells (12). Pertussis toxin and agents increasing intracellular cAMP abolished the ANG II-induced protein synthesis, indicating that the AT1-receptor is coupled to adenylate cyclase by a pertussis-toxin-sensitive Gi protein (7). The observation that this tubular hypertrophy partly depends on ANG II-mediated transcription and synthesis of transforming growth factor-b (TGF-b), was the first demonstration that the vasopeptide can induce TGF-b in the kidney (13).
Interestingly, transfection of mouse proximal tubular cells with the c-mas oncogene converts the hypertrophic growth response of ANG II into proliferation. This change is associated with decreased TGF-b transcription and synthesis in c-mas transfected cells suggesting that ANG II-mediated TGF-b transcription is pivotal for the hypertrophic growth response in proximal tubular cells (7). Tubular cells undergoing ANG II-mediated hypertrophy are arrested in the G1-phase of the cell cycle and express typical G1-phase-associated genes (7,12).
This G1-phase arrest depends on the induction of the cyclin-dependent kinase (CdK) inhibitor p27Kip1. p27Kip1 expression is stimulated after incubation of LLC-PK1 cells with ANG II or TGF-b, binds to cyclin D1-CdK4 complexes, inhibits their kinase activity, and finally hampers G1-phase exit (14). Recent observations indicate that ANG II-mediated generation of oxygen radicals may be a pivotal signal transduction pathway from ANG II-receptor activation to the induction of p27Kip1 expression and subsequent cell cycle arrest. ANG II stimulates transcription of collagen type IV in MCT cells, a mouse proximal tubular cell line (7,12). This stimulation is mediated by endogenous synthesis and autocrine action of TGF-b because a neutralizing anti-TGF-b antibody as well as TGF-b antisense oligonucleotides attenuate ANG II-induced collagen type IV transcription and synthesis (7).
We have more recently obtained evidence that ANG II additionally induces mRNA and protein expression of a3(IV)collagen which has a more restricted distribution in the kidney that the common a1 and a2(IV) chains (15). Since proximal tubular cells do normally not exhibit a3(IV)collagen, ANG II-induced expression of this chain may be considered as expression of a potential neoautoantigen on tubular cells (15).
Moreover, we have obtained evidence through a series of recent studies that ANG II exerts immunomodulatory effects on the kidney through the induction of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and RANTES (16,17). For example, ANG II stimulates the synthesis of RANTES, a member of the C-C chemokine subfamily, in cultured rat glomerular endothelial cells (GER), but not in syngeneic mesangial cells (16). Surprisingly, the ANG II-stimulated RANTES expression was transduced by the AT2-subtype of ANG II-receptors.
Intraperitoneal infusion of ANG II into naive rats for 4 days significantly stimulated glomerular RANTES mRNA and protein expression (16). Immunohistochemistry revealed induction of RANTES protein mainly in glomerular endothelial cells and small capillaries. Moreover, ANG II-infused animals exhibited an increase in glomerular infiltration of macrophages/monocytes (M/M) compared with controls. Oral treatment with an AT2-receptor antagonist attenuated the glomerular influx of such cells without normalizing the slightly elevated systolic blood pressure caused by ANG II infusion. However, the ANG II-mediated synthesis of other cytokines in the kidney such as MCP-1 may be mediated through AT1-receptors because glomerular MCP-1 mRNA and protein was significantly attenuated by AT1-receptor antagonists in a model of mesangial proliferative glomerulonephritis (17). Furthermore, AT1-receptor treatment reduced glomerular M/M influx in nephritic rats by approximately 30-50% (17). These novel results indicate that ANG II may exert immunomodulatory effects in vitro and in vivo through the induction of various chemokines in the kidney.
1. Agodoa L, Eknoyan G, Ingelfinger J, Keane W, Mauer M, Mitch W, Striker G, Wilcox C. Assessment of structure and function in progressive renal disease. Kidney Int 1997; 52 (Suppl.63): S144-S150
2. US Renal Data System: USRDS 1997 Annual Data Report. V. Patient mortality and survival. Am J Kidney Dis 1997; 30 (Suppl. 1): S86-S106
3. Mackenzie HS, Brenner BM. Current strategies for retarding progression of renal disease. Am J Kidney Dis 1998; 31: 161-170
4. Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. New Engl J Med 1996; 334: 939-945
5. The GISEN group: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: 1857-1863
6. Wolf G, Ziyadeh FN. The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 1997; 29: 153-163
7. Wolf G, Ziyadeh FN. Renal tubular hypertrophy induced by angiotensin II. Sem Nephrol 1997, 17: 448-454
8. Egido J. Vasoactive hormones and renal sclerosis. Kidney Int 1996; 49: 578-597
9. Wolf G, Neilson EG. Cellular biology of tubulointerstitial growth. Curr Topics Pathol 1995; 88: 69-97
10. Wolf G, Haberstroh U, Neilson EG. Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol 1992, 140: 95-107
11. Wolf G, Ziyadeh FN, Zahner G, Stahl RAK. Angiotensin II is mitogenic for cultured rat glomerular endothelial cells. Hypertension 1996; 27: 897-905
12. Wolf G, Neilson EG. Angiotensin II induces cellular hypertrophy in cultured murine proximal tubular cells. Am J Physiol 1990; 259: F768-F777
13. Wolf G, Mueller E, Stahl RAK, Ziyadeh FN. Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-b. J Clin Invest 1993; 92: 1366-1372
14. Wolf G, Stahl RAK. Angiotensin II-stimulated hypertrophy of LLC-PK1 cells depends on the induction of the cyclin-dependent kinase inhibitor p27Kip1. Kidney Int 1996; 50: 2112-2119
15. Wolf G, Kalluri R, Ziyadeh FN, Neilson EGStahl RAK. Angiotensin II induces a3 (IV) collagenexpression in cultured proximal tubular cells. Proc Assoc Am Phys 1999, 111: 357-364
16. Wolf G, Ziyadeh FN, Thaiss F, Tomaszewski J, Caron RJ, Wenzel U, Zahner G, Helmchen U, Stahl RAK. Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest 1997; 100: 1047-1058
17. Wolf G, Schneider A, Helmchen U, Stahl RAK. AT1-receptor antagonists abolish glomerular MCP-1 expression in a model of mesangial proliferative glomerulonephritis. Exp Nephrol 1998; 6: 112-120.
Introduction
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