PGI2 Analog Attenuates Salt-Induced Renal Injury through the Inhibition of Inflammation and Rac1-MR Activation.

Daigoro Hirohama,Wakako Kawarazaki,Nobuhiro Ayuzawa,Mitsuhiro Nishimoto,Shigeru Shibata,Toshiro Fujita,Takeshi Marumo

doi:10.3390/ijms21124433

Abstract

Renal inflammation is known to be involved in salt-induced renal damage, leading to end-stage renal disease. This study aims to evaluate the role of inflammation in anti-inflammatory and renoprotective effects of beraprost sodium (BPS), a prostaglandin I2 (PGI2) analog, in Dahl salt-sensitive (DS) rats. Five-week-old male DS rats were fed a normal-salt diet (0.5% NaCl), a high-salt diet (8% NaCl), or a high-salt diet plus BPS treatment for 3 weeks. BPS treatment could inhibit marked proteinuria and renal injury in salt-loaded DS rats with elevated blood pressure, accompanied by renal inflammation suppression. Notably, high salt increased renal expression of active Rac1, followed by increased Sgk1 expressions, a downstream molecule of mineralocorticoid receptor (MR) signal, indicating salt-induced activation of Rac1-MR pathway. However, BPS administration inhibited salt-induced Rac1-MR activation as well as renal inflammation and damage, suggesting that Rac1-MR pathway is involved in anti-inflammatory and renoprotective effects of PGI2. Based upon Rac1 activated by inflammation, moreover, BPS inhibited salt-induced activation of Rac1-MR pathway by renal inflammation suppression, resulting in the attenuation of renal damage in salt-loaded DS rats. Thus, BPS is efficacious for the treatment of salt-induced renal injury.

Highlights

Dietary high-salt intake does increase blood pressure and induce renal injury
We have demonstrated that salt loading increases Rac1 activity in the kidneys of Dahl salt-sensitive (DS) rats, which is associated with mineralocorticoid receptor (MR) activation and upregulation of the MR target gene serum and glucocorticoid-regulated kinase (Sgk1) expression despite reduced circulating levels of aldosterone, a ligand of MR, resulting in salt-induced kidney injury [7]
Rac1 and MR activities were appropriately decreased by salt loading in Dahl salt-resistant (DR) and normotensive rats, which were not accompanied by kidney injury [7]

Summary

Introduction

Dietary high-salt intake does increase blood pressure and induce renal injury. Accumulating evidence indicates that inflammation in the kidney plays a key role in salt-induced renal damage, leading to end-stage renal disease [1,2,3]. N-acetyl-seryl-aspartyl-lysyl-proline, a natural tetrapeptide with anti-inflammatory properties, prevented salt-induced renal damage without affecting the blood pressure in Dahl salt-sensitive (DS) rats [4]. It is still unknown how inflammation evoked by a high-salt diet leads to renal injury. Rac1-MR activation plays a key role in mediating salt-induced kidney injury in DS rats

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Results