Cardiorenal syndrome (CRS) indicates a condition in which the heart and the kidney communicate the status of each other’s organs through crosstalk [1]. The factors involved in cardiorenal syndrome are many humoral factors, sympathetic nerve systems, blood flow, and blood pressure. CRS is divided into five subgroups, each with a different pathogenesis. CRS type 1 is a rapidly worsening heart failure followed by acute renal failure; CRS type 2 is chronic heart failure followed by progressive chronic kidney disease (CKD); CRS type 3 is acute renal failure followed by acute heart failure; CRS type 4 is chronic renal failure followed by chronic heart failure; and CRS type 5 is organ failure followed by combined heart and kidney dysfunction [1]. Decreased renal blood flow has been thought to be an important factor in the pathogenesis of CRS2. Changes in the nervous system, such as the sympathetic nervous system [2], and humoral factors such as the angiotensin-aldosterone system [3] are also thought to be important factors. Recently, anemia due to decreased erythropoietin has also been considered an important factor in the pathogenesis of the child [4]. On the other hand, clinical observations suggest that increased kidney venous pressure, rather than decreased cardiac output, plays a crucial role in deteriorating kidney function in heart failure patients [5]. However, there are controversies as to whether renal venous dilatation or the elevated renal interstitial hydrostatic pressure by renal congestion is the aggravating factor.

This study by Ito et al. shed a light on the relationship between renal congestion and renal tubulointerstitial fibrosis [6]. This article contributes to the analysis of the pathogenesis of CRS type 2 among them. To investigate this, they performed experiments with normal and elevated renal interstitial hydrostatic pressure (RIHP) in renal congestion in high-salt-fed Dahl salt-sensitive (DahlS) rats with capsulated or decapsulated kidneys. in which decapsulated and capsulated kidneys. Pericytes are specialized cells located on the walls of capillaries and play a crucial role in maintaining microvascular stability and regulating blood flow. They hypothesized that increased RIHP due to renal congestion could contribute renal injury, pericyte detachment, and pericyte-myofibroblast transition in high-salt-fed DahlS rats. They revealed that pericyte detachment occurred mainly in the vasa recta of the capsulated kidneys of high-salt-fed DahlS rats, particularly evident in the electron microscopy. This detachment was associated with renal congestion and was significantly reduced by reducing RIHP with renal decapsulation, indicating that the elevation of RIHP is critically important factor in detachment of pericytes rather than dilatation of vasa recta in the kidney (Fig. 1).

Fig. 1
figure 1

Pericyte detachment was observed in the vesa recta of capsulated kidney with elevated renal interstitial hydrostatic pressure (RIHP) in high-salt-fed DahlS rats. In contrast, decapsulation of the kidney with normalized RIHP ameliorated detachment of pericyte and renal tubulointerstitial fibrosis in these rats

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They also investigated changes in mRNA expression related to extracellular matrix production (Acta2, Cnn1, and Fn1), tubular injuries (Havcr1, and Spp1), and pericyte-myofibroblast transition (Pdgfra, Pdgfrb, and Taglin), which were increased in capsulated kidney of high-salt-fed DahlS rats, and attenuated by renal decapsulation. Theses results also indicate that the degree of pericyte detachment is associated with expression of these markers. Histological analysis also confirmed the presence of renal fibrosis, tubular injury, and pericyte-myofibroblasts transition markers in the right capsulated kidneys of high-salt-fed DahlS rats. These findings were consistent with the molecular results and supported the role of elevation of RIHP in these pathological changes.

A more interesting aspect in this article is the examination of human kidney samples, particularly in patients with heart failure, a condition associated with renal congestion. Their observations showed pericyte detachment in the kidneys of patients with heart failure, suggesting that pericyte abnormalities are not limited to animal models but also occur in clinical situations associated with renal congestion. PDGFRB protein, a pericyte marker, was increased in the interstitial space around the vasa recta in patients with heart failure, supporting the involvement of pericytes in renal congestion-related pathophysiology in humans. The study’s results suggest that pericyte detachment and pericyte-myofibroblast-transition induced by increased RIHP are responsible for tubulointerstitial injury and fibrosis in DahlS rats and humans with renal congestion. This insight into the pathophysiology of renal congestion-related renal damage will deepen the understanding of the role of pericytes and their detachment in renal congestion-related damage in patients with heart failure.

However, the mechanism of kidney dysfunction in the setting of renal congestion also needs to be discussed from a different aspect than the increased hydrostatic pressure discussed in this article. Kitani et al. investigated the mechanism that increased renal venous pressure causes the deterioration of kidney function in heart failure [7]. They found that the decrease of blood flow velocity and the activation of NF-κB signaling are important factors in the exacerbation of kidney injury. They conducted experiments using a novel mouse model of unilateral kidney congestion to explore these mechanisms. They showed dilatation of peritubular capillaries and reduced blood flow velocity in the congested kidney, by using intravital images. Furthermore, ischemia-reperfusion injury was more severe in the congested kidney, with an accumulation of polymorphonuclear leukocytes within peritubular capillaries. The study also investigated the effects in vitro, where they found that polymorphonuclear leukocyte adhesion to activated endothelial cells decreased with flow velocity but was canceled by the inhibition of NF-kB signaling. Pharmacological inhibition of NF-κB in mice subjected to both kidney congestion and ischemia-reperfusion injury ameliorated the accumulation of polymorphonuclear leukocytes and subsequent kidney injury. Therefore, analysis of the blood flow velocity and activation of NF-κB signaling in this article will provide further insight into the pathogenesis. These factors seem to be involved in the detachment of pericytes and interstitial fibrosis. These factors may also be associated with reduced renal blood flow in the pathogenesis of CRS type 2, suggesting that both renal congestion and reduced renal blood flow may be important in the actual clinical setting. As activation of NF-κB has been shown to be involved in inflammatory, more precise investigation of microinflammation in the setting of chronic heart failure is necessary. In the future experiments, it is interesting to investigate whether decapsulation has effects on renal venous blood flow velocity and activation of NF-κB signaling.

This study reveals the intricate relationship between renal congestion, pericyte morphology, and pericyte-myofibroblast transition in a rat model and provides clinical evidence of pericyte detachment in human kidney samples from heart failure patients. These findings contribute to our understanding of the mechanisms underlying renal damage in cardiorenal syndrome and offer potential targets for therapeutic intervention.