Direct Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage

Müller, Dominik N.; Luft, Friedrich C.

doi:10.2215/cjn.01201005

Cited by 120 publications

(118 citation statements)

References 48 publications

(37 reference statements)

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“…The STZ-induced diabetic model is not a hypertensive model; therefore, the therapeutic effects seen in this study are blood pressure-independent. The efficacy of the RAS-targeting drugs is often compromised by the reactive renin increase caused by disruption of the renin feedback inhibition (26,32). This clinical problem is not solved even with the use of the new renin inhibitor aliskiren (39), which blocks the enzymatic activity but not the production of renin.…”

Section: Discussionmentioning

confidence: 99%

“…Although RAS inhibitors, including ACEIs and ARBs, are widely used in the therapy of renal and cardiovascular diseases, the major problem of these drugs is the compensatory renin rise due to the disruption of the feedback inhibition of renin production (26). The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28).…”

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confidence: 99%

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Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Zhang

Ning

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

261

225

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The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We albuminuria ͉ glomerulosclerosis ͉ renin-angiotensin system D iabetic nephropathy is the most common renal complication that often leads to end-stage kidney disease and high mortality (1). Previous studies have suggested the renin-angiotensin system (RAS) as a major mediator of progressive renal injury in diabetic nephropathy. Drugs targeting the RAS including angiotensin (Ang)-converting enzyme inhibitors (ACEIs) and Ang II type 1 receptor blockers (ARBs) have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (2-6). The systemic components of the RAS are actually down-regulated in diabetic mellitus (7), whereas renal interstitial Ang II levels are estimated to be 1,000-fold higher than in the plasma (8); therefore, intrarenal RAS is thought to play the major damaging role. In fact, all components of the RAS are present within the kidney (9). Cells in the kidney are able to synthesize renin, prorenin/renin receptor (10), angiotensinogen, and Ang II receptors independent of the systemic RAS (11), making the kidney capable of maintaining a high level of intrarenal Ang II. Intrarenal renin and angiotensinogen levels are induced in diabetic animals (12, 13), and high glucose has been shown to stimulate renin and Ang II synthesis in mesangial cells and podocytes (14-16). Intrarenal Ang II exerts multiple effects on the kidney that promote the progression of renal injury; these include an increase in glomerular capillary pressure, induction of profibrotic and proinflammatory cytokine production, promotion of immune cell infiltration, stimulation of cell proliferation and hypertrophy, up-regulation of extracellular matrix (ECM) synthesis, and damaging of podocytes (17)(18)(19) (21), and null mutant mice lacking the vitamin D receptor (VDR) gene develop hyperreninemia, high blood pressure, and cardiac hypertrophy (22)(23)(24). Our recent studies showed that in diabetic state VDR-null mice developed more severe nephropathy than wild-type mice (25), suggesting that vitamin D plays a protective role against hyperglycemia-induced renal injury by regulation of the RAS. However, whether vitamin D or vitamin D analogs have therapeutic effects in intervention or prevention of diabetic nephropathy remains to be tested.Although RAS inhibitors, including ACEIs and ARBs, are widely used in the therapy of renal and cardiovascular diseases, the major problem of these drugs is the compensatory renin rise due to the disruption of the feedback inhibition of renin production (26). The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28). The increased renin can also act through the...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Zhang

Ning

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

261

225

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“…Tetapi, pada dekade terakhir terjadi peningkatan kejadian gagal jantung kronis dan ESRD (End Stage Renal Disease). Ada beberapa faktor penyebab diantaranya adalah kurang optimalnya strategi pencegahan dan pengobatan hipertensi, sehingga perlu penelitian lebih lanjut untuk menemukan obat baru yang lebih baik untuk penderita hipertensi esensial [1].…”

Section: Pendahuluanunclassified

“…Dalam perkembangan selanjutnya telah ditemukan beberapa senyawa yang mempunyai efek sebagai renin inhibitor dan memiliki bioavailabilitas yang cukup baik sehingga dapat dikembangkan sebagai obat. Salah satu senyawa yang banyak diteliti adalah aliskiren [1].…”

Section: Pendahuluanunclassified

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Aliskiren, Obat Antihipertensi Baru dengan Mekanisme Penghambat Renin

Holidah

2011

J. Trop. Pharm. Chem.

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Hypertension is a chronic disease with a prevalence reaching ABSTRAKHipertensi merupakan salah satu penyakit kronis dengan prevalensi mencapai 1 milyar jiwa di seluruh dunia. Hipertensi yang menginduksi penyakit kardiovaskular merupakan penyebab utama kematian di dunia. Pengaturan tekanan darah hingga optimal masih sulit untuk dicapai di semua Negara. RAAS merupakan target utama, walaupun begitu, penghambatan RAAS secara total tidak dapat diperoleh dengan penggunaan obat golongan ACEI dan ARB karena adanya mekanisme umpan balik. Sebagai solusinya, dapat dilakukan penghambatan pada tahap awal dari mekanisme tersebut yaitu pada renin. Penelitian sebelumnya sudah mengindikasikan bahwa obat golongan renin inhibitor efektif sebagai antihipertensi dan dapat ditoleransi dengan baik, baik sebagai monoterapi maupun dikombinasi dengan obat lain. Berdasarkan penelitian yang sudah dilakukan terhadap aliskiren serta keberhasilan obat antihipertensi golongan ACEI dan ARB dalam menurunkan angka morbiditas dan mortalitas pada penderita hipertensi, maka sangat rasional jika diharapkan obat golongan renin inhibitor seperti aliskiren akan memberikan manfaat yang sama. Apakah manfaat tersebut sama, lebih besar atau justru lebih kecil daripada yang ditunjukkan oleh inhibitor RAAS yang lain, maka diperlukan penelitian lain yang panjang untuk mencari data pendukung.

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Adsorption, Distribution, Metabolism, Excretion (ADME), Efficacy, and Toxicology for BACE Inhibitors

Hussain

Demont

2010

Bace

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Direct Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage

Cited by 120 publications

References 48 publications

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Aliskiren, Obat Antihipertensi Baru dengan Mekanisme Penghambat Renin

Adsorption, Distribution, Metabolism, Excretion (ADME), Efficacy, and Toxicology for BACE Inhibitors

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