Renal Farnesoid X Receptor improves high fructose-induced salt-sensitive hypertension in mice by inhibiting DNM3 to promote nitro oxide production

Abstract

Objective:Farnesoid X Receptor (FXR) is highly expressed in renal tubules, activation of which attenuates renal injury by suppressing inflammation and fibrosis. However, whether renal FXR contributes to the regulation of blood pressure (BP) is poorly understood. This study aimed to investigate the anti-hypertensive effect of renal FXR on high-fructose-induced salt-sensitive hypertension and underlying mechanism.Methods:Hypertension was induced in male C57BL/6 mice by 20% fructose in drinking water with 4% sodium chloride in diet (HFS) for 8 weeks. The effects of FXR on NO production were estimated in vitro and in vivo.Results:Compared with control, HFS intake elevated BP, enhanced renal injury and reduced renal NO levels as well as FXR expression in the kidney of mice. In the mouse renal collecting duct cells mIMCD-K2, FXR agonists promoted NO production by enhancing the expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), whereas this effect was diminished by fxr knockdown. We further found that Dynamin 3 (DNM3), a binding protein with nNOS in the renal medulla, was inhibited by FXR and its deficiency elevated NO production in mIMCD-K2 cells. In HFS-fed mice, renal fxr overexpression significantly attenuated hypertension and renal fibrosis, regulated the expression of DNM3/nNOS/iNOS, and increased renal NO levels.Conclusion:Our results demonstrated that renal FXR prevents HFS-induced hypertension by inhibiting DNM3 to promote NO production. These findings provide insights into the role and potential mechanism of renal FXR for the treatment of hypertension.

Renal lysophospholipase A1 contributes to Enterococcus faecalis-induced hypertension by enhancing sodium reabsorption

“…It is unclear whether LYPLA1 contributes to increase BP in these different hypertensive animals. We notice that the serum level of Ang II is increased in Ang II, E. faecalis (the present work and ( Zhu et al., 2021 )), and HFS treatment ( Chen et al., 2020a ; Zhu et al., 2022 ) but inhibited in DOCA/salt ( Basting and Lazartigues, 2017 ) and Dahl models ( Pelisch et al., 2011 ). These imply that LYPLA1 may respond to risk stimulators other than Ang II, such as high salt or aldosterone.…”

“…The kidney and urine samples of Ang II-infused, DOCA/salt-fed rats or high-fructose plus salt-fed (HFS) mice were received from our previous studies( Chen et al., 2020b ; Zhang et al., 2019 ; Zhu et al., 2022 ). The urine samples were collected for the following examination.…”

Identification of ferroptosis-related diagnostic markers in primary Sjögren's syndrome based on machine learning

“…Our results revealed significant differences in the gene expression profiles of pSS samples compared to normal samples, with 1,830 significantly up-regulated genes and 1,310 significantly down-regulated genes. Notably, we found that DNM3 and UNC13D were up-regulated, both of which have been reported to be associated with overactivation of the immune system ( 15 , 16 ), suggesting that pSS may progress due to immune system overactivation. Additionally, our enrichment analysis showed significant activation of calcium signaling pathway and extracellular matrix organization, which are consistent with previous reports ( 17 , 18 ).…”

The role of the farnesoid X receptor in kidney health and disease: a potential therapeutic target in kidney diseases

“…In a recent study, C57BL/6 mice with hypertension induced by 20% fructose in drinking water with 4% sodium chloride (HFS) in the diet for 8 weeks had increased blood pressure; they also had decreased renal NO levels and FXR expression. Intrarenal FXR overexpression in HFS-fed mice and FXR agonist treatments in mIMCD-K2 cells attenuate hypertension and promote NO production by regulating the expression of dynamin 3 (DNM3), which is a binding protein with neuronal NOS in the renal medulla 27 . Overall, studies have been conducted on sodium modulation by bile acids and blood pressure regulation by FXR agonists; however, further studies are needed to evaluate the mechanisms and therapeutic potential of FXR and bile acid receptors.…”