Sympathetic Nerve Activation in Acute Kidney Injury and Cardiorenal Syndrome

Acute kidney injury (AKI) is a syndrome characterized by a rapid decline of renal function in combination with renal tissue injury. The incidence of AKI in critically ill patients is as high as 40–60% [1, 2], and dialysis-requiring AKI is associated with a very high mortality rate of approximately 50% [3]. Although many promising therapeutics have been suggested by basic studies [4], no drug has been shown to be effective for human AKI. On the other hand, recent findings suggest that organ interactions in AKI may be a good target for therapeutic intervention [5]. The interactions between the kidney and heart are well recognized as cardiorenal syndromes (CRSs) [6]. Activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) and venous congestion in acute or chronic heart failure are considered to induce kidney injury. In addition, recent animal studies reported that activation of the cholinergic anti-inflammatory pathway, which involves the vagus nerve, has a protective effect on kidney injury [7].

The SNS plays an important role in the kidneys. The sympathetic nerves innervate the blood vessels in the kidneys. When the SNS is activated, vasoconstriction in the renal arteries occurs, resulting in blood flow reduction to the kidneys. In addition, the SNS stimulates the release of renin from juxtaglomerular cells and subsequently activates the RAAS. This promotes sodium reabsorption and increases systemic blood pressure. Chronic sympathetic overactivity contributes to the development of hypertension. Inappropriate sympathetic activation is known to be associated with the development and progression of drug-resistant hypertension. Renal denervation (RDN) is a neuromodulation therapy against drug-resistant hypertension. An updated meta-analysis of randomized placebo-controlled trials of RDN reported a significant reduction in ambulatory and office blood pressure, although the magnitude of the benefit is modest [8].

In addition to increasing blood pressure and RAAS activation, sympathetic nerve activation is assumed to induce renal injury via other mechanisms. An experimental study reported that RDN attenuates renal fibrosis after unilateral ureteral obstruction [9]. Local infusion of norepinephrine into denervated kidneys increases transforming growth factor-β1 (TGF-β1) expression, interstitial expression of α-smooth muscle actin (α-SMA), and excessive deposition of extracellular collagen matrix. Similar findings were observed in another animal model of ischemia/reperfusion injury (IRI) [10]. IRI-induced tubulointerstitial fibrosis observed 4–16 days after the injury was attenuated by RDN at the time of injury or up to 1 day post-injury. Treatment with afferent nerve-derived calcitonin gene-related peptide or efferent nerve-derived norepinephrine in denervated and IRI-induced kidneys mimicked innervation.

In contrast to hypertension and chronic interstitial fibrosis in the kidney, several animal studies reported the protective role of sympathetic nerve activation on AKI. A specific and long-acting β2-adrenergic receptor agonist, formoterol, was identified as a potent inducer of mitochondrial biogenesis in the kidney [11]. Animal experiments evaluating the efficacy of formoterol to restore mitochondrial and kidney function in renal IRI showed that treatment with formoterol restored renal function, rescued renal tubular epithelial injury, together with increased mitochondrial biogenesis by formoterol [12]. Hasegawa and colleagues investigated the role of sympathetic signaling in macrophages in lipopolysaccharide-induced sepsis and the renal IRI model [13]. In vitro analysis revealed β2-adrenergic receptor (Adrb2) activation in macrophages induced the expression of T-cell Ig and mucin domain 3 (Tim3), which is known as anti-inflammatory phenotypic alterations. In vivo, β2 stimulation by salbutamol inhibited lipopolysaccharide-induced inflammatory reactions. Moreover, salbutamol treatment significantly reduced renal injury caused by IRI, and these protective effects were canceled in macrophage-specific Adrb2 conditional knockout mice, and adoptive transfer of salbutamol-treated macrophages protected against renal IRI. Furthermore, single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue.

CRSs are defined with five different phenotypes. Among them, CRS type 1, in which AKI occurs complicated by acute decompensated heart failure, is reportedly associated with high rates of mortality and hospitalization in heart failure [14]. In CRS type 2, chronic heart failure induces kidney injury, which is presented as chronic kidney disease [15]. In a clinically relevant murine model of nonischemic hypertrophic CHF, transverse aortic constriction (TAC), increased serum creatinine concentration, and increased kidney injury marker 1 (KIM-1) protein expression together with focal tubulointerstitial and perivascular fibrosis were observed in the kidneys at 12 weeks [16].

It is assumed that sympathetic nerve activation may have some role in kidney injury in acute and chronic heart failure. As described above, sympathetic nerve activation seems to have dual effects on AKI and chronic renal fibrosis. However, little is known about whether sympathetic nerve activation will be protective in CRS. To clarify the role of sympathetic nerve activation in CRS, we conducted an animal experiment, using the combining models of TAC and unilateral renal IRI [17]. The evaluation of acute (24 h) and chronic (2 weeks) phases of renal injury following IRI 8 weeks after TAC surgery revealed that no impact was observed in the acute phase of renal IRI, while the development of renal fibrosis in the chronic phase was significantly attenuated by preexisting heart failure. We performed RDN 2 days prior to renal IRI, which abrogated attenuation of renal fibrosis in TAC mice. Therefore, it could be concluded that the protective effect of preexisting heart failure on chronic renal interstitial fibrosis may be mediated via sympathetic nerve activation. Although sympathetic activation is assumed to be a contributor to enhancing renal recovery after IRI under pressure overload on the heart, it should be noted that attenuation of renal fibrosis by preexisting heart failure by TAC was observed in RSDN mice. These data indicate that mechanisms other than sympathetic activation are involved.

Sympathetic nerve activation in kidney injury is protective in AKI and harmful in chronic renal fibrosis. However, it seems to be different in the more complicated and clinically relevant situation of CRS. Under the condition of heart failure, sympathetic nerve activation was shown to be protective in chronic renal fibrosis, though further studies are needed to prove that activation of adrenergic receptors are protective for chronic renal fibrosis under heart failure (Table 1; Fig. 1). This underscores that a better understanding of the role of SNS is necessary to translate basic research findings into the clinical practice. Recent animal studies reported the protective role of the cholinergic anti-inflammatory pathway for kidney injury [7]. In this pathway, the stimulation of the vagus nerve by inflammatory cytokines activates the splenic nerve, resulting in the activation of macrophages, suppressed proinflammatory cytokine production, and ameliorating AKI, though it is unknown whether the activity of the pathway affects chronic fibrosis after AKI. Integrated analysis of both the sympathetic nerve system and the parasympathetic nerve system will provide new insights for clarifying mechanisms of communication between the nervous system and the kidney.

The authors have no conflicts of interest to declare.

Research reported in this publication was supported by KAKEN-HI 20K09284 (to K.D.) and 20K17274 (to R.M.), MEXT, Japan.

Kent Doi and Ryo Matsuura prepared all manuscript drafts and were involved in reviewing and editing, including the table. Kent Doi and Ryo Matsuura approved the final version of the manuscript.