Role of the renin angiotensin system in diabetic nephropathy

Abstract

Diabetic nephropathy has been the cause of lot of morbidity and mortality in the diabetic population. The renin angiotensin system (RAS) is considered to be involved in most of the pathological processes that result in diabetic nephropathy. This system has various subsystems which contribute to the disease pathology. One of these involves angiotensin II (Ang II) which shows increased activity during diabetic nephropathy. This causes hypertrophy of various renal cells and has a pressor effect on arteriolar smooth muscle resulting in increased vascular pressure. Ang II also induces inflammation, apoptosis, cell growth, migration and differentiation. Monocyte chemoattractant protein-1 production responsible for renal fibrosis is also regulated by RAS. Polymorphism of angiotensin converting enzyme (ACE) and Angiotensinogen has been shown to have effects on RAS. Available treatment modalities have proven effective in controlling the progression of nephropathy. Various drugs (based on antagonism of RAS) are currently in the market and others are still under trial. Amongst the approved drugs, ACE inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. ARBs are shown to be superior to ACE inhibitors in terms of reducing proteinuria but the combined role of ARBs with ACE inhibitors in diabetic nephropathy is under debate.

Key Words: Diabetic nephropathy; Angiotensin II; Monocyte chemoattractant protein-1; Renin angiotensin system

INTRODUCTION

Diabetic nephropathy is the leading cause of end stage renal disease (ESRD). It is also a leading cause of diabetes mellitus-related morbidity and mortality worldwide. Pathogenesis of diabetic nephropathy is related to uncontrolled or chronic hyperglycemia. It is characterized by hypertrophy of glomeruli, hyperperfusion, thickening of basement membranes and glomerular hyperfiltration[1]. In addition there is microalbuminuria and subsequently progressive glomerulosclerosis. Later, tubulointerstitial fibrosis occurs causing reduction in glomerular filtration rate (GFR)[2,3].

The purpose of this article is to give an insight into the involvement of renin angiotensin system (RAS) in diabetic nephropathy. It highlights various pathophysiological, genetic and inflammatory issues related to RAS in diabetes.

RENIN-ANGIOTENSIN PHYSIOLOGY

The RAS present in the kidneys, is comprised of angiotensinogen, renin, angiotensin I (Ang I), angiotensin converting enzyme related carboxypeptidase (ACE2), angiotensin converting enzyme, angiotensin II (Ang II), aldosterone, Ang II type 1 receptor (AT1R) and the Ang II type 2 receptor (AT2R).

Renin is a proteolytic enzyme produced by juxtaglomerular cells in the kidney. Renin acts on angiotensinogen to form Ang I which then gets converted to Ang II by angiotensin-converting enzyme (ACE)[4] present in many tissues (particularly the pulmonary vascular endothelium). Ang II is a pressor agent and exerts its action by direct effect on arteriolar smooth muscle causing increased vascular pressure. In addition it stimulates production of aldosterone by the zona glomerulosa of the adrenal cortex which helps in sodium reabsorption in the kidney. The heptapeptide angiotensin III may also stimulate aldosterone production.

When blood volume is low, angiotensin causes blood vessels to constrict resulting in increased blood pressure and release of aldosterone. In the kidneys, efferent arterioles are constricted more than afferent, forcing blood to build up in the glomerulus and increasing glomerular pressure. The GFR is thus maintained, and blood filtration can continue despite lowered kidney blood flow.

In addition to circulating renin-angiotensin, many tissues like uterus, placenta, vascular tissue, heart, brain, and, particularly, the adrenal cortex and kidney have a local RAS[5,6]. Although the role of locally generated Ang II is not established, it may modulate the growth and function of the adrenal cortex and vascular smooth muscle[5,6].

Ang II is also a potent growth modulator and proinflammatory peptide. In addition, this peptide degrades bradykinin, a vasodilator[7]. A chemically related enzyme, ACE-related carboxypeptidase, also known as ACE2, has recently been cloned and identified by two different groups[8,9]. ACE2 has 42% homology with ACE at the metalloprotease catalytic domain[4-6] but differs from ACE in having only one enzymatic site. In humans, ACE2 transcripts have been identified in the heart, kidney, and testis[8,10]. Shiota et al[11] suggests that ACE2 might prevent both glomerular and tubulointerstitial injury in diabetic nephropathy.

The possible role of RAS has been studied for changes in intraglomerular hemodynamics[7] as well as structural changes in the diabetic kidney at both the glomerular and tubulointerstitial levels[7,12].

PATHOPHYSIOLOGY OF DIABETIC NEPHROPATHY

Diabetic nephropathy starts with glomerular hyperperfusion and renal hypertrophy causing increase in GFR[5,6]. Subsequently, microalbuminuria develops which if not checked will progress to macroalbuminuria and a decline in GFR will result.

During the disease process the increased Ang II activity causes hypertrophy of mesangial cells and tubular epithelial cells[13]. It also promotes production of the prosclerotic cytokine transforming growth factor-beta (TGF-β) which has been identified as one of cause for glomerular sclerosis[13,14].

Some groups of researchers have found that tubular epithelial cells in diabetes induce kidney monocyte chemoattractant protein-1 (MCP-1) production which is regulated by RAS[15,16]. This MCP-1 is responsible for macrophage recruitment resulting in renal fibrosis and indirect promotion of extracellular matrix formation. By observing the role of MCP-1 in the pathophysiology of diabetic nephropathy we can undoubtedly say that it is a promising therapeutic target for treating diabetic nephropathy[15,16].

Oxidative stress-sensitive nuclear factor κB (NFκB) activation and up-regulation of the proinflammatory genes MCP-1 and regulated on activation, normal T-cell expressed and secreted (RANTES)[17] have been observed to be related to proteinuria and interstitial cell infiltration, adding further insult to the kidney. Zhernakova et al also found that in type 1 diabetes, RANTES, a T-helper type 1 (Th1) chemokine, promotes activation and proliferation of T-cells[17,18]. Cortical tubular epithelial cells, podocytes, and some renal mononuclear cells have also shown NFκB activity.

ROLE OF ANG II

During inflammation, macrophages and lymphocytes can generate reactive oxygen species and Ang II[19]. Diabetic nephropathy being an inflammatory condition, Ang II levels have been found to be elevated[19]. This rise activates immune cells and causes production of chemokines[20] leading to further renal damage. The increased ACE and Ang II expression in tubular, interstitial and fibroblast-like cells has been seen with immunostaining. These, together with high glucose and inflammatory mediators, target tubular cells causing deranged kidney functions in diabetes[21]. Ang II has also been shown to activate and upregulate NFκB and related genes[20].

As discussed earlier, Ang II is a major hormone of the RAS and contributes to a variety of renal and cardiovascular physiologic and pathologic mechanisms. Some authors have found that Ang II in the kidney generates reactive oxygen species (ROS) and promotes podocyte autophagy by enhancing podocyte expression of autophagic genes, LC3-2 and beclin-1[22].

Ang II causes renal vascular vasoconstriction via AT1R. The role of AT2R has been discussed by various investigators and shown to be favorable for vascular health. The beneficial effects include decrease in blood pressure, inhibition of cell growth, apoptosis[23], antiproliferative and anti-inflammatory actions[24]. AT2R has been seen to be upregulated by insulin and insulin like growth factor-1 (IGF-1)[25,26] and downregulated by Ang-II, epidermal growth factor (EGF), platelet derived growth factor (PDGF)[27] and in diabetes[23,28]. AT2R has also been seen to be upregulated in various clinical conditions such as Na⁺ depletion, renal ischemia reperfusion[29]. Alhough the exact regulation mechanism of AT2R in diabetic nephropathy is unknown, immunohistochemistry (IHC) has shown low expression of AT2R in diabetes mellitus[23].

Recently, Siragy demonstrated the role of AT₂ receptors in vasodilation, nitric oxide and cGMP production[30] which is beneficial in curbing damage. He therefore suggested the development of specific AT2R agonists to add to the treatment regimen for diabetic nephropathy. Though AT₁ and AT₂ receptors usually have opposite effects they are actually similar in inhibiting renin production with AT₂ achieving this via bradykinin-nitric oxide-cGMP vasodilatory pathway[30-32].

ROLE OF POLYMORPHISM

The distribution of ACE insertion/deletion (I/D) polymorphism in type-2 diabetes mellitus (DM) has been studied by various investigators[33,34]. The II genotype has a better response to ACE inhibitors particularly at normoalbuminuria or microalbuminuria levels[35]. In DD genotype patients with overt nephropathy, antirenin angiotensin therapy was shown to be effective whereas in males having nondiabetic proteinuric nephropathies ACE inhibitors were effective[35]. An older study including 2890 patients with type 1 diabetes associated nephropathy showed them to be predisposed to coronary artery disease[34] while relatively new research by Marre et al[36] with 494 subjects revealed no such association with ACE polymorphism.

Angiotensinogen (AGT) polymorphism also has effects on the RAS system. Some researchers have found association of methionine 235 with threonine (M235T), a T to C base substitution at position 702 on exon 2 with consequent replacement of M235T, with progression of diabetic nephropathy[37,38], in agreement with data from 95 nephropathy patients taken by Fogarty et al[39]. However, studies by Tarnow et al[40] (195 nephropathy patients) and Doria et al[41] (305 patients having either microalbuminuria or proteinuria) found no relation of AGT polymorphism with diabetic nephropathy. More studies need to be conducted to consolidate the role of AGT polymorphism in diabetic nephropathy.

BLOCKADE OF RAS IN DIABETIC NEPHROPATHY

The importance of RAS has been highlighted time after time and this system has a central role in the pathophysiology of diabetic nephropathy. Hypertension usually accompanies diabetes mellitus, early in type 2 and delayed in type 1. Worsening of diabetic nephropathy is rapid when there is progression from normoalbuminuria to macroalbuminuria, a transition which takes about ten years. With increasing albumin excretion the risk of renal and cardiovascular disease deepens[42,43]. In patients with diabetic nephropathy, lowering of blood pressure and urinary albumin excretion significantly decreases the risk of progression to ESRD, myocardial infarction and stroke[44].

ACE inhibitors decrease the production of Ang II, which is a potent vasoconstrictor, leading to lower intraglomerular pressure and reduced glomerular hypertension. They also decrease the glomerular permeability to urinary albumin leading to decreased proteinuria[45].

ARBs act by blocking Ang II type 1 receptors (AT₁ receptors). This AT₁ blockade may lead to further increase in synthesis of Ang II which binds to intrarenal AT₂ receptors, resulting in decreased blood pressure[46] and reduced renal interstitial fibrosis[47].

Proteinuria better responds to ARBs than ACE inhibitors[48,49]. Treatment with captopril and olmesartan has been shown to be beneficial in experimental models of diabetic albuminuria and podocyte injury[50,51]. In children also, addition of ARBs further reduces renal injury without affecting blood pressure[52]. The diabetics exposed to telmisartan and enalapril (DETAIL) study concluded that telmisartan is non-inferior to enalapril in renoprotection and is associated with a low incidence of mortality[53].

Combined therapy with both ACE inhibitors and ARBs has been shown by some to be more beneficial in terms of reducing proteinuria, blood pressure and cardiovascular morbidity and mortality[54-57]. In contrast, the recently concluded ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET, 25 620 patients) and the telmisartan randomised assessment study in ACE intolerant subjects with cardiovascular disease (TRANSCEND, 5926 patients) studies came to different conclusions[58,59].

ONTARGET trial found marginal reduction in systolic blood pressure with combination therapy. No significant benefit in terms of myocardial infarction (MI), hospitalization for heart failure or death from cardiovascular or non-cardiovascular causes was detected[58].

The TRANSCEND study again observed slight reduction of blood pressure with telmisartan but the differences in the primary end-point of MI, stroke, hospital admission with heart failure were not statistically significant compared to placebo[59]. A review by Shinichiro Ueda again highlighted the unsolved question of whether dual blockade of RAS will benefit patients[60].

Recently a direct renin blocker has been invented that blocks RAS (Aliskiren), thus allaying the fear of reactive elevation of renin encountered while using ACEI or ARBs. Aliskiren’s reno-protective properties have been observed in patients with diabetic as well as non-diabetic nephropathy[61]. Aliskiren in the evaluation of proteinuria in diabetes (AVOID) study observed that aliskiren, in addition to optimising blood pressure treatment in hypertension, also reduces the mean urinary albumin-to-creatinine ratio in patients with type 2 diabetes and nephropathy[62].

CONCLUSION

Diabetes is a multisystem disorder and involvement of the kidney is a major cause of hospitalization and infirmity among the diabetic population. RAS has been proved to be the torch bearer in pathogenesis of diabetic nephropathy. Various other factors including polymorphism, inflammatory mediators and cytokines combined with patient unawareness and non-compliance results in serious damage to renal functions in diabetes.

To date, various trials have shown arrest of the disease process and improvement in the condition of patients in the disease population through blockade of RAS although none achieved complete block. Further trials should be conducted at the molecular and genetic level to find better ways to stop insult caused by RAS to the diabetic kidney.