Association between renin-angiotensin system inhibitor and the risk of CMV pneumonia:a Mendelian randomization study

Background:Cytomegalovirus(CMV)reactivation is linked to a high mortality rate,especially among the elderly.Prior research suggests that renin-angiotensin system(RAS)inhibitors may influence both the onset and prognosis of pneumonia.This study aims to examine the causal relationship between RAS inhibitor use and the risk of CMV pneumonia using Mendelian randomization(MR)analysis.Methods:We conducted an analysis using data from two genome-wide association studies(GWAS)involving individuals of European ancestry.This dataset included individuals treated with RAS inhibitors and those with CMV pneumonia.We assessed the relationship between RAS inhibitor use and CMV pneumonia risk using the inverse variance weighted(IVW)method.The results were further evaluated for pleiotropy,heterogeneity,and robustness.Results:The Mendelian randomization(MR)analysis revealed a causal relationship between RAS inhibitor use and an increased risk of CMV pneumonia(IVW:odds ratio[OR]=2.73;95%confidence interval[CI]=1.11-6.73;P=0.028).Conclusions:Our finding indicate a positive causal relationship between the use of RAS inhibitors and the onset of CMV pneumonia.

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.

Role of the renin angiotensin system in diabetic nephropathy

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.

Renin angiotensin system in liver diseases: Friend or foe?

In the last three decades,the understanding of the renin angiotensin system(RAS)has been changed by the discoveries of functional local systems,novel biologically active peptides,additional specific receptors,alternative pathways of angiotensin(Ang)?Ⅱ?generation,and new roles for enzymes and precursor components other than those in Ang?Ⅱ?synthesis.In this regard,the discovery that Ang-(1-7)opposes the pressor,proliferative,pro-fibrotic,and pro-inflammatory effects mediated by Ang?Ⅱ?has contributed to the realization that the RAS is composed of two axes.The first axis consists of the angiotensin-converting enzyme(ACE),with Ang?Ⅱ?as the end product,and the angiotensin type 1(AT1)receptor as the main effector mediating the biological actions of Ang?Ⅱ.The second axis results from ACE2-mediated hydrolysis of Ang?Ⅱ,leading to the production of Ang-(1-7),with the Mas receptor as the main effector conveying the vasodilatory,antiproliferative,anti-fibrotic,and anti-inflammatory effects of Ang-(1-7).Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases.In this manuscript,we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications,including hemodynamic changes and hepatorenal syndrome.The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.

Inflammation, oxidative stress and renin angiotensin system in atherosclerosis

Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.

Therapeutic potential of targeting the renin angiotensin system in portal hypertension

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

What have we learned about the kallikrein-kinin and renin-angiotensin systems in neurological disorders?

The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.

Calcium channel blocker monotherapy versus combination with reninangiotensin system inhibitors on the development of new-onset diabetes mellitus in hypertensive Korean patients

Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.

Nonalcoholic fatty liver disease and the renin-angiotensin system:Implications for treatment

Nonalcoholic fatty liver disease(NAFLD) is the commonest liver disease in Western countries.Treatment of NAFLD is currently based on lifestyle measures and no effective pharmacologic treatment is available so far.Emerging evidence,mainly from animal studies,suggests that the renin-angiotensin-aldosterone system may be of major importance in the pathogenesis of NAFLD and indicates that angiotensin-converting enzyme inhibitors(ACE-I) and angiotensin receptor blockers(ARBs) as a potentially useful therapeutic approach.However,data from human studies are limited and contradictory.In addition,there are few randomized controlled trials(RCTs) on the effects of ACE-I or ARB in patients with NAFLD and most data are from retrospective studies,pilot prospective studies and post hoc analyses of clinical trials.Accordingly,more and larger RCTs are needed to directly assess the effectiveness of ACE-I and ARBs in NAFLD.

Renin Angiotensin System Components and Cancer: Reports of Association

Renin-Angiotensin System (RAS) is involved with hypertension and other cardiovascular diseases. However, the association of RAS components to cancer still causes suspicion. To try to clarify this, here we aimed to show this association for three important components: Angiotensin Converting Enzyme 1 (ACE1), Angiotensin Type 1 Receptor (AGTR1) and Angiotensin Type 2 Receptor (AGTR2). The first articles show that association of RAS components with cancer dates back to the 70’s. ECA1 and AGTR1 have close association with cancer and ACE1 inhibitors or AGTR1 blockers are candidates to treatment of some tumors. Moreover, the action of AGTR2 is still controversial, but most studies show that the increased expression of AGTR2 can attack the cancer cells. In breast cancer, these components have also been widely studied and many works have shown that the correlation exists. Therefore specific target using these RAS components could be a beneficial, novel therapy to various tumors.

Prominent Roles of the Renin Angiotensin System in Atherosclerosis

The renin angiotensin system (RAS) is emerging as a prominent factor in the development of experimental atherosclerosis. We have previously demonstrated that the RAS is profoundly activated in hypercholesterolemia. This was demonstrated in LDLR-/-mice fed a saturated fat enriched diet and manifested as increased plasma concentrations of angiotensinogen and angiotensin peptides; especially angiotensin Ⅱ (AngⅡ).

Inhibition of the Renin-Angiotensin System and Cardiovascular Mortality in Chronic Hemodialysis Patients

INTRODUCTION: Since the outcomes associated with the use of renin-angiotensin-system inhibitors (RASi) by hemodialysis (HD) patients are not fully known, we investigated their effect on the cardiovascular mortality of chronic HD patients. METHODS: Data from 388 HD patients (237 men and 151 women) who were routinely treated for at least 6 months were analyzed. Treatment with a RASi was the major predictor variable. The main outcome measure was cardiovascular mortality. Cox regression analysis was used to assess for the use of RASi and risk of death. RESULTS: Hypertension was diagnosed in 320 patients (82.5%), and 197 (50.8%) of them were treated with a RASi (treated group) and 191 (49.2%) were not (untreated group). The treated group had a higher prevalence of hypertension, history of congestive heart failure, and presence of ST-T changes. Kaplan-Meier analysis revealed a reduction in risk of cardiovascular death in the treated group during the follow-up period (fig. 2;log-rank: p=0.0379). The multivariate analysis showed that treatment with a RASi was also independently associated with reduced cardiovascular mortality (hazard ratio= 0.184;p=0.0161). CONCLUSIONS: The results of this study suggest a possible association between the treatment with RASi and reduced risk of cardiovascular mortality, independent of their effect of lowering blood pressure.

Renin-Angiotensin System and Thrombosis

Considerable evidence has accumulated to support the concept that the effects of the renin-agniotensin system can be mediated through two modes: endocrine and paracrine modes.

Effects of highly potent atrial natriuretic peptide on circulating reninangiotensin-aldosterone system and cardiac function in dogs with ischemic heart failure

The effects of highly-potent atrial natriuretic peptide (HPANP) on circulating re nin-angiotensin-aldos-terone system (RAAS) and cardiac function were studied in an acute ischemic heart failure model. HPANP (6 μg/kg and 3 μg/kg) was infused intracoronarily. It was found that both doses of HPANP could cause significant decrease in plasma renin activity (PRA), angiotensin II (AII) and aldosterone (Ald). After the administraticn of HPANP, PRA, AII and Ald in the coronary sinus were decreased by 73. 2% (P<0.01), 68. o% (P<0.01) and 73. 6% (P<0.01), and the hormones in peripheral venous blood by 63. 3% (P<0.01), 53. 3% (P<0.01) and 64. 9% (P<0.01), respectively at the dose of 6 μg/kg. While PRA, AII and Ald in the coronary sinus and in peripheral venous blood decreased by 55. 9%, 55. 3%, 61. 9%, and 54. 0%, 42. 3%, 53, 3%, respectively at the 3μg/kg dose level. At the higher dose, HPANP increased left ventricular systolic pressure (LVSP, +13. 1%, P<0. 05), +dP/dtmax(+24.1 %, P<0.01), -dp/dtmax (+35.9%, P<0.01), and VCE(+28.9%, P<0.05). Mean arterial pressure and left ventricular end-diastolic pressure (LVEDP) were decreased (-15.0%, P<0.01, and 29. 6%, P<0.01, respectively). In contrast, the lower dose caused no significant changes of LVSP, +dp/dtmex,dp/dtmax and VCE(not including LVEDP, - 20. 5 %, P<0.05). Neither of the doses caused significant changes in heart rate and T value- Normal saline infusion has no effects on cardiac function and circulating RAAS- We conclude that in ischemic heart failure, intracoronary administration of HPANP can significantly suppress the activity of circulating RAAS, and improve cardiac function by reducing pre- and after-load of the heart, but has no direct myocardial effects.

Effect of Topical Propranolol Gel on Plasma Renin,Angiotensin Ⅱ and Vascular Endothelial Growth Factor in Superficial Infantile Hemangiomas

The effect of topical propranolol gel on the levels of plasma renin,angiotensin Ⅱ（ATⅡ） and vascular endothelial growth factor（VEGF） in superficial infantile hemangiomas（IHs） was investigated. Thirty-three consecutive children with superficial IHs were observed pre-treatment,1 and 3 months after application of topical propranolol gel for the levels of plasma renin,AT Ⅱand VEGF in Department of General Surgery of Dongfang Hospital from February 2013 to February 2014. The plasma results of IHs were compared with those of 30 healthy infants of the same age from out-patient department. The clinical efficiency of topical propranolol gel at 1st,and 3rd month after application was 45%,and 82% respectively. The levels of plasma renin,AT and VEGF in patients preⅡ-treatment were higher than those in healthy infants（565.86±49.66 vs. 18.19±3.56,3.20±0.39 vs 0.30±0.03,and 362.16±27.29 vs. 85.63±8.14,P〈0.05）. The concentrations of VEGF and renin at 1st and 3rd month after treatment were decreased obviously as compared with those pre-treatment（271.51±18.59 vs. 362.16±27.29,and 405.18±42.52 vs. 565.86±49.66 P〈0.05; 240.80±19.89 vs. 362.16±27.29,and 325.90±35.78 vs. 565.86±49.66,P〈0.05,respectively）,but the levels of plasma AT declined slightly Ⅱ（2.96±0.37 vs. 3.20±0.39,and 2.47±0.27 vs. 3.20±0.39,P〉0.05）. It was indicated that the increased renin,AT Ⅱand VEGF might play a role in the onset or development of IHs. Propranolol gel may suppress the proliferation of IHs by reducing VEGF.

The Comparison Study of Renin and Angiotensin AⅡ Levels on Normal Tension Glaucoma Patients and Normal Individuals

Purpose: To investigate the levels of renin-angiotension system (RAS) components in normal tension glaucoma patients and normal controls. Methods: Blood samples were obtained from 11 normal tension glaucoma(NTG)patients and 11 age and sex matched controls. The levels of renin and angiotensin AⅡof 11 NTG patients and normal controls were examined by radio-immunity test. Statistical analyses were performed by paired t test. Results:The levels of renin of NTG patients and normal controls are (769.085±183.217) pg/ml/n and (822.035 ±124.140) pg/ml/n, while the levels of angiotensin A Ⅱof NTG patients and normal controls are (37.347±10.669)pg/ml and (24.836±10.665)pg/ml respectively. No statistically significant differences were observed between the levels of renin and angiotensin among NTG patients and normal controls. Conclusion: There were not many abnormalities of the levels of circulating rennin and angiotensin AⅡof NTG patients in our study. Eye Science 2005 ;21 :192-195.

Serum levels of angiotensin converting enzyme as a biomarker of liver fibrosis

The renin angiotensin system(RAS) is classically conceived as a circulating hormonal system involved in blood pressure control and hydroelectrolyte balance. The discovery that RAS components are locally expressed in a wide range of organs and tissues,including the liver,pointed to a role for this system in the pathogenesis of several conditions including hepatic fibrosis and cirrhosis. It has been widely reported that the classical RAS axis composed by the angiotensin converting enzyme(ACE)-angiotensin(Ang) Ⅱ-Ang type 1(AT1) receptor mediates pro-inflammatory,pro-thrombotic,and pro-fibrotic processes. On the other hand,the alternative axis comprising ACE2-Ang-(1-7)-Mas receptor seems to play a protective role by frequently opposing Ang Ⅱ action. Chronic hepatitis B(CHB) is one of the leading causes of liver fibrosis,accounting for the death of nearly one million people worldwide. Liver fibrosis is a key factor to determine therapeutic interventions for patients with CHB. However,the establishment of non-invasive and accurate methods to detect reversible stages of liver fibrosis is still a challenge. In an elegant study published in the 36 th issue of the World Journal of Gastroenterology,Noguchi et al showed the predictive value of serum ACE levels in detecting not only advanced stages of liver fibrosis but also initial and intermediate fibrotic stages. The serum levels of ACE might represent an accurate,non-invasive,widely available,and easy method to evaluate fibrosis related to CHB. Moreover,therapies involving the inhibition of the classical RAS axis components might be promising in the control of CHB-related liver fibrosis.

Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease

Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H2O2) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H2O2-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease.

Pericytes synthesize renin

AIM： To investigate renin expression in pericytes dur-ing normal kidney development and after deletion of angiotensinogen, the precursor for all angiotensins.METHODS： We examined the distribution of renin ex-pressing cells by immunoshistochemistry in the intersti-tial compartment of wild type （WT） and angiotensino-gen deficient （AGT -/-） mice at different developmental stages from embryonic day 18 （E18： WT, n = 4; AGT -/-, n = 5） and at day 1 （P1： WT, n = 5; AGT -/-, n = 5）, 5 （P5： WT, n = 7; AGT -/-, n = 8）, 10 （P10： WT, n = 3; AGT -/-, n = 5）, 21 （P21： WT, n = 7; AGT -/-, n =5）, 45 （P45： WT, n = 3; AGT -/-, n = 3）, and 70 （P70： WT, n = 2; AGT -/-, n = 2） of postnatal life. We quanti-fied the number of pericytes positive for renin at all the developmental stages mentioned above and compared the results of AGT -/- mice to their WT counterparts.RESULTS： In WT mice, renal interstitial pericytes syn-thesize renin in early life supporting a lineage relation-ship with renin cells in the vasculature. The number of pericytes positive for renin per area of 0.32 mm2 （density） in WT mice was maintained from fetal life till weaning age （E18 = 4.25 ± 0.63, P1 = 3.75 ± 0.48, P5 = 3.75 ± 0.48, P10 = 4 ± 0.71, P21 = 3.8 ± 0.58） and markedly decreased in adult life （P45 = 1.2 ± 0.37, P70 = 0.8 ± 0.20）. On the other hand, in AGT -/- mice the density of pericytes expressing renin was not signifi-cantly different from WT mice at E18 and P1： E18 = 5.75 ± 0.50 vs 4.25 ± 0.63 （ P = 0.106）, P1 = 9.25 ± 3.50 vs 3.75 ± 0.48 （ P = 0.175） but significantly increased from P5 till P70： P5 = 38.25 ± 5 vs 3.75 ± 0.48 （ P = 0.0004）, P10 = 173 ± 7.50 vs 4 ± 0.70 （ P = 5.24567 × 10^-7）, P21 = 83 ± 6.70 vs 3.8 ± 0.58 （P = 2.97358 × 10^-6）, P45 = 49 ± 3.50 vs 1.2 ± 0.37 （P = 8.18274 × 10^-7） and P70 = 17.8 ± 2.30 vs 0.8 ± 0.20 （ P = 3.51151 × 10^-5）. The AGT -/- mice showed a marked increase in the number of pericytes per field studied starting from P5, reaching its peak at P10, and then a gradually de-creasing until P70.CONCLUSION： Interstitial pericytes synthesize renin during development and the number of renin-express-ing pericytes increases in response to a homeostatic threat imposed early in life such as lack of angioten-sinogen.

Inhibition of renin activity by aliskiren ameliorates diabetic nephropathy in type 1 diabetes mouse model

Renin is the rate-limiting enzyme of the reninangiotensin system (RAS). In addition to its enzymatic activity to generate angiotensin I, renin also signals through the (pro)renin receptor to exert angiotensin II-independent effects. In this study we examined the effect of renin inhibition on the development of diabetic nephropathy. Male DBA/2J mice were induced to diabetes with streptozotocin, and the diabetic mice were treated for 16 weeks with saline or aliskiren, a renin enzymatic inhibitor. Aliskiren treatment had little effects on blood glucose and blood pressure in diabetic mice. Saline-treated mice developed progressive albuminuria and glome-rulosclerosis, and aliskiren treatment effectively alleviated albumiuria and glomerulosclerosis. Morphologically aliskiren treatment prevented the thickening of the glomerular basement membrane and reduced podocyte loss. At the molecular levels, aliskiren prevented the decline of slit diaphragm proteins and blocked the synthesis of extracellular matrix and pro-fibrotic factors in the diabetic kidney. Aliskiren treatment results in compensatory renin increase in the glomeruli due to blockade of the negative feedback loop, and also partially suppressed the intracellular signaling mediated by the (pro)renin receptor activated in hyperglycemia. These observations suggest that the therapeutic activity of aliskiren to prevent diabetic renal injury is contributed by inhibition of both the angiotensin II-dependent and -independent pathways. Taken together, it is concluded that inhibition of renin enzymatic activity ameliorates diabetic renal injury in type 1 diabetes, and support the use of aliskiren in diabetes kidney disease.