Inhibition of the Renin-Angiotensin System in Chronic Kidney Disease: A Critical Look to Single and Dual Blockade

Locatelli, Francesco; Vecchio, Lucia Del; Cavalli, Andrea

doi:10.1159/000235946

Cited by 23 publications

(19 citation statements)

References 71 publications

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“…It has been well established that the activation of RAS is hazardous, leading to the progression of CKD. [36][37][38] Therefore, numerous RAS inhibitors, such as direct renin inhibitor, angiotensin-converting enzyme inhibitors, angiotensin II receptor type 1 blockers, and/or aldosterone blockers, have been administered to patients with CKD. [36][37][38] The importance of RAS inhibitors in the treatment of CKD is without doubt, but the high prevalence of CKD in an era of RAS inhibitors indicates that it is necessary to develop new renoprotective strategies with therapeutic mechanisms independent of RAS inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38] Therefore, numerous RAS inhibitors, such as direct renin inhibitor, angiotensin-converting enzyme inhibitors, angiotensin II receptor type 1 blockers, and/or aldosterone blockers, have been administered to patients with CKD. [36][37][38] The importance of RAS inhibitors in the treatment of CKD is without doubt, but the high prevalence of CKD in an era of RAS inhibitors indicates that it is necessary to develop new renoprotective strategies with therapeutic mechanisms independent of RAS inhibition. [39][40][41] If the main renoprotective mechanism of active vitamin D was renin suppression, therapeutic potential of active vitamin D would be severely limited, because direct renin inhibitor (aliskiren) is currently available.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…The primary aims of treatment in patients with CKD are both to prevent or, at least slow, progression of CKD. However, available therapies are limited and include inhibitors of renin/angiotensin system (Locatelli et al, 2009;Morrow et al, 2010). However, these drugs are not able to completely block the progression.…”

Section: Suramin Inhibits Progression Of Renal Fibrosis 763mentioning

confidence: 99%

“…Given the high prevalence of CKD and cost of replacement therapies for ESRD, any treatment that halts or slows the progression of renal fibrosis has the potential to provide an immense medical, social, and economic benefit. At present, angiotensinconverting enzyme inhibitors and angiotensin II receptor type 1 blockers are clinically used to combat renal fibrosis (Locatelli et al, 2009;Morrow et al, 2010). However, these drugs are not able to completely stop the progression of renal fibrosis; in some conditions, such as aristolochic acid-induced renal fibrosis in rats, they are not effective at all (Debelle et al, 2004;Boor et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Liu

Tolbert²,

Ponnusamy³

et al. 2011

J Pharmacol Exp Ther

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We recently showed that suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further assessed the effect of delayed administration of suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of ␣-smooth muscle actin (␣-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-␤ (TGF-␤) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of suramin suppressed TGF-␤1-induced expression of ␣-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of suramin as an antifibrotic treatment in patients with chronic kidney disease.

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“…tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest.…”

mentioning

confidence: 99%

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

Nath

Hernandez

Croatt

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/ injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest. In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3, 4, 11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.An established approach employed in studying the pathogenetic basis for ANG II-induced renal injury utilizes the chronic administration of ANG II by osmotic minipumps. Such studies demonstrate that ANG II, so administered, provokes markedly i...

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Inhibition of the Renin-Angiotensin System in Chronic Kidney Disease: A Critical Look to Single and Dual Blockade

Cited by 23 publications

References 71 publications

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

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

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

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