Renal Inflammation in DOCA-Salt Hypertension

Abstract

Recent reports indicate that, in addition to treating hypertension, renal denervation (RDN) also mitigates renal inflammation. However, since RDN decreases renal perfusion pressure, it is unclear whether these effects are due to the direct effects of RDN on inflammatory signaling or secondary to decreased arterial pressure (AP). Therefore, this study was conducted to elucidate the contribution of renal nerves to renal inflammation in the DOCA-salt rat, a model in which RDN decreases AP and abolishes renal inflammation. In Experiment 1, we assessed the temporal changes in renal inflammation by measuring renal cytokines and AP in DOCA-salt rats. Uninephrectomized (1K) adult male Sprague Dawley rats that received surgical renal denervation (RDN) or sham (Sham) were administered DOCA (100mg, s.c.) and 0.9% saline for 21 days. AP was measured by radiotelemetry, and urinary cytokine excretion were measured repeatedly. In Experiment 2, the contribution of renal nerves in renal inflammation was assessed in a 2-kidney DOCA-salt rat to control for renal perfusion pressure. DOCA-salt treatment was administered after unilateral (U-)RDN. In Experiment 1, DOCA-salt induced increases in AP and renal inflammation (assessed by urinary cytokines) were attenuated by RDN versus Sham. In Experiment 2, GRO/KC, MCP-1, and macrophage infiltration were lower in the denervated kidney vs. the contralateral Sham kidney. No differences in T-cell infiltration were observed. Together, these data support the hypothesis that renal nerves mediate, in part, the development of renal inflammation in the DOCA-salt rat independent of hypertension. The mechanisms and cellspecificity mediating these effects require further investigation.

ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway

“…During this process, kidney is a major organ for BP homeostasis. Recently, there is a growing body of evidence suggesting that inflammation plays a crucial role in the progression of salt-sensitive hypertension as well as kidney dysfunction 3 – 5 . In experimental models, salt-sensitive hypertension are associated with the accumulation and activation of T cells in the kidney, which produces inflammatory cytokines including IFN-γ, IL-17, and TNF-α; results in sodium retention, vasoconstriction and enhanced oxidative stress; and then promotes hypertension, glomerular injury, renal fibrosis, and dysfunction 6 .…”

Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice

“…The mechanisms responsible for the antihypertensive effect of RDNX are still unclear. Our laboratory and others have previously reported that specifically targeting afferent renal nerves in DOCA-salt model 35 – 37 or efferent nerves in Dahl salt sensitive rats 24 chronically lower MAP. Similar studies would be necessary to identify which type of renal nerves (afferent or efferent) are important in BPH/2J mice.…”

Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

“…However, there is conflicting evidence concerning the distinctive contribution of renal afferent and efferent nerves on the described anti-inflammatory effects of RDN. Xiao et al (2015) could not find a contribution of afferent nerves on Ang II-induced hypertension and renal inflammation, whereas Banek showed evidence that renal afferent nerves modulate at least in part renal inflammation in DOCAsalt hypertension (Banek et al, 2016(Banek et al, , 2019. In another study, performed in global α2A-deficent mice chronically infused with a high dose of Ang II, increased renal sympathetic norepinephrine release impairs renal function and aggravates hypertension as well as renal fibrosis without affecting the amount of infiltrating immune cells (Hering et al, 2020).…”

“…In hypertension as well as acute or chronic kidney damage, stimulation of renal nociceptive afferent nerves mediate an increase in sympathetic nerve activity leading to a further activation of RSNA and subsequently to a progression of hypertension and hypertensive kidney disease. Thus, several other factors such as pro-inflammatory cytokines ( Banek et al, 2019 ), uremic toxins ( Campese and Kogosov, 1995 ), and hypoxia ( Dibona and Kopp, 1997 ; Soukhova-O'hare et al, 2006 ; Saha et al, 2019 ) can activate the chemo- and mechano-sensitive afferent nerves leading to an increased RSNA. Activation of afferent nerves under pathophysiological conditions such as acute kidney injury induced by a phenol injection into the kidney causes hypertension by increasing RSNA via afferent renal nerve stimulation ( Ye et al, 2002a , b ; Leong et al, 2006 ).…”

“…In another study, performed in global α2A-deficent mice chronically infused with a high dose of Ang II, increased renal sympathetic norepinephrine release impairs renal function and aggravates hypertension as well as renal fibrosis without affecting the amount of infiltrating immune cells ( Hering et al, 2020 ). At first glance, these results seem to be conflicting as several studies have shown that increased RSNA activates a pro-inflammatory immune cell response leading to immune cell infiltration and an aggravation of renal fibrosis and hypertension ( Kim and Padanilam, 2013 , 2015 ; Xiao et al, 2015 ; Banek et al, 2019 ). However, α2-adrenoceptors also seem to regulate immune cell function, and activation of α2-adrenoceptors seems to induce a pro-inflammatory immune response ( Scanzano and Cosentino, 2015 ).…”