Renin Inhibition

Fisher, Naomi D.L.; Hollenberg, Norman K.

doi:10.1681/asn.2004100874

Cited by 158 publications

(132 citation statements)

References 44 publications

(46 reference statements)

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“…ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; RAAS, reninangiotensin aldosterone system; T2DM, type 2 diabetes mellitus. Renin inhibitor-binding pockets on the active site of renin [135,136]. Panel A represents the ribbon and band structure with the medication aliskiren overlying the binding pocket S1/S3 and extension into the hydrophobic S3 subpockets, which allows for the prerequisite higher affinity binding necessary for the desired clinical response.…”

Section: Resultsmentioning

confidence: 99%

“…ARBs competitively inhibit the binding of Ang II to the AT 1 receptor [134]. Renin inhibitors, a new class of recently introduced drugs, block the first and rate-limiting step of the RAAS cascade, the conversion of angiotensinogen to Ang I, by binding tightly to the S1/S3 pocket of renin and the hydrophobic subpocket S3 sp ( Figure 9) [135,136]. Results from several large outcome trials conducted with ACE inhibitors or ARBs (Table 4) suggest that RAAS inhibition may be the most effective strategy for preventing or delaying T2DM in patients with hypertension [7].…”

Section: Raas Blockade Introductionmentioning

confidence: 99%

“…The therapeutic potential of renin inhibition has been investigated for many years, but a new class of orally active, nonpeptide, low-molecular-weight renin inhibitors has been developed [135,177]. Direct renin inhibitors block the RAAS at its initial point of activation.…”

Section: Direct Renin Inhibitors Introductionmentioning

confidence: 99%

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Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Hayden

Sowers

2008

Journal of the American Society of Hypertension

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Hypertension, a multifactorial-polygenic disease, interacts with multiple environmental stressors and results in functional and structural changes in numerous end organs, including the cardiovascular system. This can result in coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, end-stage renal disease, insulin resistance, and damage to the pancreatic islet. Hypertension is the most important modifiable risk factor for major health problems encountered in clinical practice. Whereas hypertension was once thought to be a medical condition based on discrete blood pressure readings, a new concept has emerged defining hypertension as part of a complex and progressive metabolic and cardiovascular disease, an important part of a cardiometabolic syndrome. The central role of insulin resistance, oxidative stress, endothelial dysfunction, metabolic signaling defects within tissues, and the role of enhanced tissue renin-angiotensin-aldosterone system activity as it relates to hypertension and type 2 diabetes mellitus is emphasized. Additionally, this review focuses on the effect of hypertension on functional and structural changes associated with the vulnerable pancreatic islet. Various classes of antihypertensive drugs are reviewed, especially their roles in delaying or preventing damage to the vulnerable pancreatic islet, and thus delaying the development of type 2 diabetes mellitus.

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Section: Resultsmentioning

confidence: 99%

Section: Raas Blockade Introductionmentioning

confidence: 99%

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Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Hayden

Sowers

2008

Journal of the American Society of Hypertension

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“…7,8 Several lines of studies revealed the renin-suppressive effect of 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. [9][10][11][12] In addition to 1,25(OH) 2 D, a less-calcemic analog, paricalcitol, has been revealed to suppress renin in the kidney.…”

mentioning

confidence: 99%

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

Inoue

Matsui

Hamano

et al. 2012

Laboratory Investigation

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Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-b1 (TGF-b1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-b1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-b1, pSmad3 bound to the proximal promoter region of the TGF-b1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-b1 increased both the nuclear levels of protein phosphatase Mg 2 þ /Mn 2 þ -dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-b1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3-dependent production of TGF-b1. Our findings provide a novel approach to inhibit the TGF-b pathway in fibrotic diseases. Tubulointerstitial fibrosis (TIF) is the final common pathway for most forms of progressive kidney diseases. 1-3 Numerous studies revealed that two major signaling pathways, the renin-angiotensin system (RAS) and the transforming growth factor-b1 (TGF-b1)/Smad system, have important roles in the pathogenesis of TIF. [3][4][5][6] However, because satisfactory therapeutic strategies have not been established, TIF remains one of the major problems in nephrology.One of the candidates that protect the kidney from TIF is active vitamin D because it is a negative regulator of renin. 7,8 Several lines of studies revealed the renin-suppressive effect of 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. [9][10][11][12] In addition to 1,25(OH) 2 D, a less-calcemic analog, paricalcitol, has been revealed to suppress renin in the kidney. 13 These findings provide a rationale for active vitamin D therapy in renal diseases with high local renin.

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“…6 Renin inhibitors block the RAS at the very origin. 7,8 Although all these drug classes inhibit the RAS, actions on the various components of the system differ (Table 1).…”

Section: Blockade Of the Renin Angiotensin Systemmentioning

confidence: 99%