Role of angiotensin II in the progression of diabetic nephropathy therapeutic implications

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1 Nephrol Dial Transplant (2003) 18 [Suppl 5]: v16 v20 DOI: /ndt/gfg1036 Role of angiotensin II in the progression of diabetic nephropathy therapeutic implications Andrzej Wie cek, Jerzy Chudek and Franciszek Kokot Department of Nephrology, Endocrinology and Metabolic Diseases, Silesian University Medical School, Katowice, Poland Keywords: angiotensin II; diabetic nephropathy; angiotensin-converting enzyme inhibitors; angiotensin II receptor blockers Introduction During the last four decades, the renin angiotensin system (RAS) has emerged as an important endocrine factor in the chain of physiological blood pressure regulation and water electrolyte balance, and as a substantial determinant of cardiovascular and renal remodelling. For >20 years it has been established that angiotensinogen is produced in the liver, and is in turn cleaved by the proteolytic enzyme reninreleasing angiotensin I, which is converted to angiotensin II by the converting enzyme (ACE) in the lung and other organs. It is well known that this circulating RAS is suppressed in patients with diabetic nephropathy [1]. A turning point in the research on the RAS was the finding of local tissue-specific RAS in several organs. Such local systems were found not only in glomerular and tubulointerstitial cells of the kidneys but in almost all organs of the human body. Micropuncture studies of the nephron revealed 1000 times higher concentrations of angiotensin II in proximal tubular and interstitial fluid than in systemic blood [2]. What is the role of this local renal RAS systems? Under physiological conditions, the glomerular RAS is a main player in the regulation of glomerular filtration by influencing the resistance predominantly of the vasa efferentia and to a less degree of the vasa afferentia, and by altering the effective filtration surface. The tubulointerstitial RAS is presumed to stimulate sodium and bicarbonate reabsorption in proximal tubules (by activation of the luminal Na þ /H þ exchanger, basolateral Na þ /HCO 3 cotransporter and Na þ /K þ ATPase). Both systems seem to play an important role in the compensatory mechanisms induced by nephron injury. Excessive local angiotensin II concentration increases glomerular permeability by a variety of mechanisms such as a high intraglomerular transmembrane pressure, suppressed synthesis of negatively charged proteoglycans and nephrin, and enhanced synthesis of extracellular matrix components [3]. In proximal renal tubules, exposed to a protein load, increased angiotensin II synthesis induces interstitial fibrosis. There are two main angiotensin II receptors (AT 1 and AT 2 ). Both have been cloned and well characterized [3]. Most biological effects of angiotensin II (Figure 1) are mediated by the AT 1 receptor via intracellular activation of phospholipase, inhibition of adenylate cyclase and stimulation of tyrosine phosphorylation [4]. The physiological function of the AT 2 receptor is not so well elucidated; however, it is generally presumed that its activation antagonizes the effects transduced by AT 1 receptor stimulation (Figure 1). Moreover, the existence of a third type of angiotensin family receptor was recognized (AT 4 ). Stimulation of that receptor by angiotensin IV results in increased plasminogen acivator inhibitor-1 (PAI-1) synthesis in proximal tubular and endothelial cells in the kidney [5,6]. The existence of other types of receptors is still postulated. Alterations of the renin angiotensin system in diabetic nephropathy Correspondence and offprint requests to: Professor Dr Andrzej Wie cek, Department of Nephrology, Endocrinology and Metabolic Diseases, Silesian University Medical School, Katowice, ul. Francuska 20/24, Katowice, Poland. awiecek@ spskm.katowice.pl In diabetic patients, plasma renin activity is usually low in comparison with non-diabetic individuals. The cause of the low circulating renin level is related to the volume expansion, autonomic neuropathy, dimin- ß 2003 European Renal Association European Dialysis and Transplant Association

2 Role of angiotensin II in the progression of diabetic nephropathy v17 Fig. 1. The renin angiotensin system, angiotensin receptors and their action. ished conversion of prorenin to renin and low prostacycline synthesis but high lipoxygenase intrarenal production [1]. Approximately 10% of diabetic patients develop hyporeninaemic hypoaldosteronism [1]. Hyperkalaemia and tubular acidosis correctable by fludrocortisone administration are typical features of this syndrome [1]. Although plasma renin activity is low, administration of ACE inhibitors (ACEIs) or AT 1 receptor blockers (ARBs) lowers arterial blood pressure, reduces proteinuria and slows the progression of diabetic nephropathy. The explanation for these findings is only partially related to the intrarenal haemodynamic changes induced by RAS blockade (increase of renal blood flow, decrease of intraglomerular pressure and glomerular filtration fraction) [3]. Local RAS systems seem to be especially important in the mechanism of renal injury and remodelling found in patients with diabetic nephropathy. First, indirect observation suggesting activation of the intrarenal RAS in diabetic subjects was reported in 1984 by Ballerman et al. [7]. These authors demonstrated decreased density of angiotensin II receptors in the glomeruli in diabetic rats, and hypothesized that a reduced number of angiotensin II receptors was induced by increased intrarenal generation of angiotensin II [7]. Ten years later, similar observations were reported concerning AT 1 receptor density in proximal tubules [8]. Immunohistochemical studies have shown a higher ACE activity in the glomeruli and blood vessels in diabetic kidneys [9]. Thus it is not surprising that renal vasodilatation in response to ACEIs and ARBs is enhanced in this disease. Activation of the glomerular RAS system in diabetic nephropathy occurs in >80% of patients [10] and seems to be related to the high glucose concentration [11] and mechanical stress [12]. Angiotensin II production by incubated mesangial cells is increased by elevated glucose concentration in the medium [11]. High glucose and angiotensin II levels inhibit matrix degradation (inhibit mesangial cell collagenase activity) via a common intracellular pathway (activation of protein kinase C) [13] and stimulate transforming growth factor- 1 (TGF- 1 )- dependent matrix synthesis [14] (Figure 2). Both the ARB losartan [11] and anti-tgf- 1 antibody [15] block glucose-induced collagen accumulation in mesangial cells. Moreover, glucose-induced TGF- 1 secretion by mesangial cells is blocked by losartan [11]. Activation of the renal RAS in diabetic patients is the cause not only of the haemodynamic alteration

3 v18 A. Wie cek, J. Chudek and F. Kokot Fig. 2. The effect of hyperglycaemia on the circulating and local RAS and TGF- 1 production in patients with diabetic nephropathy. (glomerular hyperfiltration with subsequent proteinuria) but also of inflammatory processes leading to activation and proliferation/hypertrophy of glomerular cells (mesangial, endothelial cells, podocytes) and tubular cells, and infiltration of macrophages and lymphocytes. The latter two cell types are the sources of inflammatory mediators and growth factors; fibrogenic cytokines [interleukin (IL)-1, fibroblast growth factor (FGF), tumour necrosis factor- (TNF-), platelet-derived growth factor (PDGF), TGF- 1, platelet-activating factor (PAF), etc.] are involved in transdifferentiation of tubular cells into fibroblasts, which in turn are the cause of renal fibrosis [16] (Figure 3). Fig. 3. Angiotensin II stimulates release of growth factors through NF-B activation. Similarly, activation of the tubulointerstitial RAS may promote interstitial fibrosis by inhibiting matrix degradation and stimulating its synthesis [17]. Angiotensin II stimulates TGF- 1 synthesis, not only in mesangial cells, but also in proximal tubular cells [18]. Furthermore, TGF- 1 stimulates matrix accumulation in diabetic nephropathy and is also responsible for mesangial and tubular cell hypertrophy. Mesangial cells exposed to high glucose concentration initially show increased proliferation, which later is followed by cell cycle arrest in G 1 phase and cell hypertrophy [19]. These changes are mediated by TGF- 1 because anti-tgf- antibodies prevent these glucose-induced alterations [19]. A similar TGF- 1 - dependent mechanism is responsible for tubular cell hypertrophy [19]. The molecular explanation of this process includes induction of two cyclin-dependent kinase (CKD) inhibitors (p21 Cip1 and p27 Kip1 ) which, by reducing phosphorylation of retinoblastoma protein (prb), increase retention of the transcription factor E2F [19]. Finally, cells fail to exit the G 1 phase of the cell cycle, and hypertrophy follows [19]. As AT 1 receptor blockade decreases glucose-induced TGF- 1 release [11,18], early pharmacological intervention can prevent mesangial and tubular hypertrophy in diabetic patients. Finally, it should be mentioned that angiotensin II increases vascular oxidative stress and synthesis of reactive oxygen species (ROS), inducing oxygen

4 Role of angiotensin II in the progression of diabetic nephropathy v19 Fig. 4. Reduction of diastolic blood pressure (DBP) and the urinary albumin to creatinine ratio (UACR) in diabetic patients treated with candesartan, lisinopril or both; results of the CALM study [31]. radicals which in turn lead to a loss of bioavailability of nitric oxide [20 22]. ACEIs or AT 1 agonists for RAS blockade? A number of meta-analyses have suggested that different kinds of ACEIs inducing an identical reduction of blood pressure are more effective in decreasing albuminuria than other antihypertensive drugs [23]. In 2001, three large clinical trials with AT 1 antagonists in hypertensive patients with diabetes and proteinuria were published. Each of these studies demonstrated a beneficial effect of ARBs on the progression of diabetic nephropathy [24 26] as compared with other antihypertensive drugs and placebo. These beneficial effects of ARBs were beyond their hypotensive effect. Until now, no hard data are available documenting the greater therapeutic effectiveness of ACEIs over ARBs. An ongoing trial Diabetes Exposed to Telmisartan and Enalapril (DETAIL) study was designed to answer this question in a 5-year observation period. Why enalapril and not a long-acting ACEIwas chosen remains to be elucidated. Until results of this trial are available, we have to consider both groups as equally effective. How is more effective intrarenal RAS inhibition achieved? In patients with diabetic nephropathy, the renoprotective effect of ACEIs [27 29] and ARBs [22 24] has been well documented. In spite of these therapeutic effects in the majority of patients with diabetic nephropathy, a continuous decline of glomerular filtration rate is also unavoidable. As renal deterioration is slower in patients receiving higher doses of RAS blockers, the question arises of whether combination therapy with ACEIs plus ARBs is superior to monotherapy with these agents [30]. Mogensen et al. reported that combination of lisinopril with candesartan was more effective in microalbuminuria reduction than either drug alone [31] Figure 4. Also, irbesartan added to a previously used ACEIoffered additional renal protection (reduction of albuminuria) [32]. Recently, Agarwal et al. have shown that even a maximal dose of lisinopril is unable to normalize urinary TGF- 1 excretion [33]. Addition of losartan in this study resulted in a further decrease of urinary TGF- 1 excretion, but values were still elevated in some of these patients. There is growing evidence suggesting that dual blockade of RAS at the ACE and angiotensin II receptor level is especially beneficial in diabetic patients with hypertension resistant to a blood pressure-lowering monotherapy and in patients with a massive proteinuria [30]. The long-term renoprotective effect of such a combined therapy needs to be evaluated. Conclusions (i) (ii) (iii) Patients with diabetic nephropathy are characterized by reduced circulating and enhanced local (glomerular and tubulointerstitial) RAS. Suppression of RAS with ACEIs or ARBs shows a beneficial effect on the rate of progression of diabetic nephropathy predominantly via reduction of proteinuria and lowering of arterial hypertension. Combined therapy with an ACEIand ARB seems to be indicated in diabetic patients with hypertension resistant to monotherapy and/or massive proteinuria. References 1. Mogyorosi A, Ziyadeh FN. Diabetic nephropathy. In: Massry SG, Glassock RJ, eds. Massry & Glassock s Textbook of

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