Salt accelerates aldosterone-induced cardiac remodeling in the absence of guanylyl cyclase-A signaling

Nakagawa, Hitoshi; Somekawa, Satoshi; Onoue, Kenji; Kumazawa, Takeshi; Ueda, Tomoya; Seno, Ayako; Nakada, Yasuki; Nakano, Tomoya; Matsui, Masaru; Soeda, Tunenari; Okayama, Satoshi; Kawakami, Rika; Kawata, Hiroyuki; Okura, Hiroyuki; Saito, Yoshihiko

doi:10.1016/j.lfs.2016.09.011

Cited by 4 publications

(6 citation statements)

References 25 publications

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“…Besides systemic effects such as blood pressure reduction, a positive influence of improved renal function on the cardiovascular system and direct cardiac effects of SGLT2 inhibitors have been suggested (Lopaschuk and Verma, 2020;Silva Dos Santos et al, 2020;Vallon and Verma, 2021). Since DOCA/salt treatment (Lother et al, 2016;Cao et al, 2019) as well as genetic deletion of the natriuretic peptide receptor GC-A (Kuhn et al, 2002;Kilic et al, 2005;Nakagawa et al, 2016) not only result in renal damage but also in cardiac hypertrophy and fibrosis, expression levels of marker genes for hypertrophy (BNP) and fibrosis (α-smooth muscle actin, TGF-β, collagen types 1 and 3) were determined in the respective models. As shown in Supplementary Figure S1 a nonsignificant trend towards reduced BNP and α-smooth muscle actin gene abundance was detected in EMPA treated animals, while TGF-β and collagen expression levels were completely unaffected by EMPA, indicating that EMPA does not affect cardiac fibrosis in these disease models.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

Tauber¹,

Sinha²,

Berger³

et al. 2021

Front. Pharmacol.

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Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative. Previous studies showed that SGLT2 inhibitors reduce diabetic hyperfiltration, which is likely a key element in renoprotection. In line with this hypothesis, this study aimed to investigate the nephroprotective effects of the SGLT2 inhibitor empagliflozin (EMPA) in different mouse models with non-diabetic hyperfiltration and progressing CKD to identify the underlying diabetes-independent cellular mechanisms. Non-diabetic hyperfiltration was induced by unilateral nephrectomy (UNx). Since UNx alone does not result in renal damage, renal disease models with varying degrees of glomerular damage and albuminuria were generated by combining UNx with high NaCl diets ± deoxycorticosterone acetate (DOCA) in different mouse strains with and without genetic predisposition for glomerular injury. Renal parameters (GFR, albuminuria, urine volume) were monitored for 4–6 weeks. Application of EMPA via the drinking water resulted in sufficient EMPA plasma concentration and caused glucosuria, diuresis and in some models renal hypertrophy. EMPA had no effect on GFR in untreated wildtype animals, but significantly reduced hyperfiltration after UNx by 36%. In contrast, EMPA did not reduce UNx induced hyperfiltration in any of our kidney disease models, regardless of their degree of glomerular damage caused by DOCA/salt treatment. Consistent with the lack of reduction in glomerular hyperfiltration, EMPA-treated animals developed albuminuria and renal fibrosis to a similar extent as H2O control animals. Taken together, the data clearly indicate that blockade of SGLT2 has the potential to reduce non-diabetic hyperfiltration in otherwise untreated mice. However, no effects on hyperfiltration or progression of renal injury were observed in hypervolemic kidney disease models, suggesting that high salt intake and extracellular volume might attenuate the protective effects of SGLT2 blockers.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

Tauber¹,

Sinha²,

Berger³

et al. 2021

Front. Pharmacol.

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“…Cardiomyocyte diameters and the extent of myocardial fibrosis were determined in left ventricular sections stained with hematoxylin-eosin and periodic acid Schiff or Masson trichrome as previously described. 20 Myc was tagged with NEP in CM-NEP Tg mice. To detect Myc expression in the left ventricle, frozen tissue embedded in optimal cutting temperature compound was sectioned at 3-µm thickness and fixed with 4% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling

et al. 2021

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NEP (Neprilysin) degrades natriuretic peptides, and its inhibition is a clinically accepted target for heart failure treatment. NEP is widely expressed in various organs, including the heart. However, the pathophysiological significance of local cardiac NEP is not fully understood. To study the local function of NEP in the heart, we generated transgenic mice overexpressing NEP, specifically in cardiomyocytes (CM-NEP Tg). At baseline, CM-NEP Tg mice showed significantly lower levels of plasma ANP (atrial natriuretic peptide), plasma cGMP, and cardiac tissue cGMP versus wild-type (WT) mice. Blood pressure, heart weight, and cardiomyocyte diameter were greater in CM-NEP Tg than WT mice. There were no significant differences in interstitial fibrosis or ejection fraction. Transverse aortic constriction (TAC) surgery significantly increased left ventricular weight in WT and CM-NEP Tg mice 3 weeks post-op versus sham surgery; however, the cardiac hypertrophic response to TAC was higher in CM-NEP Tg than WT mice. Cardiac interstitial fibrosis was induced in TAC CM-NEP Tg mice, whereas TAC WT mice had none. TAC CM-NEP Tg, but not TAC WT, mice developed cardiac dysfunction secondary to TAC with echocardiography. Furthermore, administration of human ANP to raise plasma ANP levels comparable to those in WT mice neither improved the exacerbated cardiac hypertrophy and fibrosis nor recovered impaired cardiac function in CM-NEP Tg mice after TAC. In conclusion, overexpression of NEP in cardiomyocytes promoted degradation of natriuretic peptides in the heart and led to an exaggerated response of hypertrophy and fibrosis to pressure overload.

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“…prevents adverse cardiac remodeling by inhibiting the deleterious salt action on aldosterone-induced MR genomic effects in the heart [38]. Protective autocrine effects of natriuretic peptides against adverse cardiac remodeling in cardiomyocytes.…”

Section: Effect Of Natriuretic Peptides On Cardiac Remodelingmentioning

confidence: 99%

“…Moreover, aldosterone-induced cardiac remodeling was exacerbated in high-salt conditions in GC-A KO mice independent of blood pressure, whereas these changes were not observed in WT mice. This indicates that GC-A signaling prevents adverse cardiac remodeling by inhibiting the deleterious salt action on aldosterone-induced MR genomic effects in the heart [ 38 ].…”

Section: Physiological Roles Of Natriuretic Peptides: Lessons From Ge...mentioning

confidence: 99%

Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases

Nakagawa

Saito

2022

Biology

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Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases.

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Salt accelerates aldosterone-induced cardiac remodeling in the absence of guanylyl cyclase-A signaling

Cited by 4 publications

References 25 publications

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling

Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases

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