Juxtaglomerular apparatus hyperplasia under dual angiotensin blockade. A footprint of adequate RAS inhibition or a concern for renal fibrosis?

Fernández-Fernández, Beatriz; Ortíz, Alberto; Gómez-Guerrero, Carmen; Barat, A.; Martín-Cleary, Catalina; Egido, Jesús

doi:10.1186/1471-2369-13-21

Cited by 5 publications

(2 citation statements)

References 21 publications

(33 reference statements)

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“…In this study, we also found that the long-term inhibition of the RAS induced arteriolar hypertrophy in humans. Some case reports showed hypertrophy of the JG area in patients with hypertension treated with RASi ( 35 ). In a recent study of the kidneys from hypertensive patients treated with antihypertensive agents, arteriolar hypertrophy was observed in patients with RASi and not detected in patients without RASi ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans

Watanabe¹,

Martini²,

Brown³

et al. 2021

JCI Insight

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Inhibitors of the renin-angiotensin system (RAS) are widely used to treat hypertension. Using mice harboring fluorescent cell lineage tracers, single-cell RNA-Seq, and long-term inhibition of RAS in both mice and humans, we found that deletion of renin or inhibition of the RAS leads to concentric thickening of the intrarenal arteries and arterioles. This severe disease was caused by the multiclonal expansion and transformation of renin cells from a classical endocrine phenotype to a matrix-secretory phenotype: the cells surrounded the vessel walls and induced the accumulation of adjacent smooth muscle cells and extracellular matrix, resulting in blood flow obstruction, focal ischemia, and fibrosis. Ablation of the renin cells via conditional deletion of β 1 integrin prevented arteriolar hypertrophy, indicating that renin cells are responsible for vascular disease. Given these findings, prospective morphological studies in humans are necessary to determine the extent of renal vascular damage caused by the widespread use of inhibitors of the RAS.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans

Watanabe¹,

Martini²,

Brown³

et al. 2021

JCI Insight

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“…However, some studies have shown better effects for ACE inhibition over AT 1 antagonism on renal protections in diabetic patients who have features of chronic kidney disease (Baltatzi, Savopoulos, & Hatzitolios, 2011; Hsu et al, 2017; Laverman et al, 2004; Mavridis, Palmer, & Strippoli, 2016; Wu et al, 2017). In some studies, AT 1 antagonist treatment is not protective for glomerular health (Fernandez‐Fernandez et al, 2012; Nagai et al, 2020; Nakanishi et al, 2011). The discrepancies between these trials could be due to differences in experimental design and medicine used.…”

Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming by N‐acetyl‐seryl‐aspartyl‐lysyl‐proline protects against diabetic kidney disease

Srivastava

Goodwin

Kanasaki

et al. 2020

British J Pharmacology

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Background and Purpose ACE inhibitors (ACEIs) and AT1 receptor antagonists (ARBs) are first‐line drugs that are believed to reduce the progression of end‐stage renal disease in diabetic patients. Differences in the effects of ACEIs and ARBs are not well studied and the mechanisms responsible are not well understood. Experimental Approach Male diabetic CD‐1 mice were treated with ACEI, ARB, N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP), ACEI + AcSDKP, ARB + AcSDKP, glycolysis inhibitors or non‐treatment. Moreover, prolyl oligopeptidase inhibitor (POPi)‐injected male diabetic C57Bl6 mice were treated with ACEI, AcSDKP and ARB or non‐treatment. Western blot and immunofluorescent staining were used to examine key enzymes and regulators of central metabolism. Key Results The antifibrotic action of ACEI imidapril is due to an AcSDKP‐mediated antifibrotic mechanism, which reprograms the central metabolism including restoring SIRT3 protein and mitochondrial fatty acid oxidation and suppression of abnormal glucose metabolism in the diabetic kidney. Moreover, the POPi S17092 significantly blocked the AcSDKP synthesis, accelerated kidney fibrosis and disrupted the central metabolism. ACEI partly restored the kidney fibrosis and elevated the AcSDKP level, whereas the ARB (TA‐606) did not show such effects in the POPi‐injected mice. ACE inhibition and AcSDKP suppressed defective metabolism‐linked mesenchymal transformations and reduced collagen‐I and fibronectin accumulation in the diabetic kidneys. Conclusion and Implications The study envisages that AcSDKP is the endogenous antifibrotic mediator that controls the metabolic switch between glucose and fatty acid metabolism and that suppression of AcSDKP leads to disruption of kidney cell metabolism and activates mesenchymal transformations leading to severe fibrosis in the diabetic kidney.

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Vaskulopathien

Amann¹,

Büttner‐Herold²,

Kain³

2015

Pathologie

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Juxtaglomerular apparatus hyperplasia under dual angiotensin blockade. A footprint of adequate RAS inhibition or a concern for renal fibrosis?

Cited by 5 publications

References 21 publications

Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans

Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans

Metabolic reprogramming by N‐acetyl‐seryl‐aspartyl‐lysyl‐proline protects against diabetic kidney disease

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