Abstract:

Renal cancer and chronic kidney disease are two renal pathologies with very different clinical management strategies and treatment options. However, the cellular and molecular mechanisms in these two conditions are closely related. Renal physiology is adapted to a limited oxygen supply, allowing the kidney to respond significantly to hypoxia. This tightly regulated response mechanism is central to renal cancer and leads to a malignant cellular phenotype. Although elusive, the role of hypoxia in chronic kidney disease is becoming associated with fibrosis, a key factor in the decline of renal function. The current review provides a perspective on the common biological features between kidney cancer and chronic kidney disease, as well as the available and potential therapeutic approaches for both diseases.

Keywords

chronic kidney disease; kidney cancer; hypoxia; new drug modalities; biomarkers;Cistanche extraction

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Introduction

In healthy adults, both kidneys receive about 20-25% of the cardiac output. Considering the relatively small size and weight of the kidneys, they are the most perfused organ compared to other systems, receiving large amounts of high-flow oxygenated blood [1]. Nevertheless, there is a paradoxical discrepancy between the level of oxygen perfused in the kidney and its actual tissue configuration and consumption. It is estimated that only about 10% of the oxygen reaching the kidney is consumed during cellular processes. Arterial oxygen tension (pO₂) is about 100 mmHg (including the renal artery, which brings blood to the kidney) and systemic venous pO₂ is about 30 mmHg. In blood flowing out of the kidney via the renal vein, pO₂ is about 70 mmHg. The reason behind this physiological property is the special structure of the renal vascular system [2]. The renal arteries and veins branch in parallel, where small arteries and veins are arranged side by side in close proximity [3]. This system allows oxygen to diffuse from the small arteries to the veins, rarely through the capillary network, thus limiting the concentration of oxygen in the surrounding tissues. The nephron - the functional unit responsible for renal secretion - is exposed to different levels of pO₂. In the renal cortex (outer zone), glomeruli and varices have higher pO₂ levels than in the renal medulla (inner zone), about 30 and 10 mmHg, respectively. it can be said that the renal pulsatile system evolved to favor the secretory function of the kidney at the expense of oxygen distribution to the 3tissues[4].

The kidney is a metabolically demanding organ that requires significant energy output to fulfill its role in blood filtration and reabsorption. The post-glomerular filtration process is dependent on a series of membrane-bound transport proteins that are expressed in both proximal and distal convoluted tubules and are responsible for the removal of metabolic biologics and xenobiotics, as well as the reabsorption of solutes, water, glucose, amino acids, and micronutrients [5]. In particular, the proximal tubules of the kidney can concentrate various compounds at steep concentration gradients [6]. The highly specialized renal proximal tubular epithelial cells (RPTEC) remove drugs and toxins from the blood while recovering large amounts of glucose and sodium from the filtrate back into the systemic circulation. RPTECs are rich in mitochondria and are responsible for the production of adenosine triphosphate (ATP) needed to power their active transport mechanisms. Due to the high rate of aerobic respiration and limited oxygen supply, renal cells have been operating under potentially unstable pO₂ conditions [7]. Therefore, the kidney is often referred to as a hypoxic organ due to its low pO₂. Hypoxia occurs when oxygen consumption exceeds supply, and renal cells have developed remarkable adaptations to operate at borderline oxygen levels. A complex regulatory mechanism maintains a delicate balance between energy expenditure and oxygen supply, preventing the kidney from falling into an actual hypoxic state in which normal physiological processes are no longer ensured.

The purpose of this review is to provide a perspective on how pathophysiological aspects common to kidney cancer and chronic kidney disease influence their diagnosis, the development of prospective therapies, and the discovery of novel biomarkers.

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Regulating the Oxygen Supply to the Kidneys

The central mechanism of the cellular response to fluctuating O₂ levels is the activity of the prolyl hydroxylase-hypoxia-inducible factor (PHD-HIF) axis. This interaction acts as a cellular O₂ sensor because a PHD consumes intracellular O₂ to catalyze the hydroxylation of HIF, a nuclear transcription factor that regulates gene expression. HIFs activity is controlled by sustained PHD-mediated hydroxylation [8]. When physiological O₂ levels are maintained (normoxia), hydroxylated HIF is degraded by protein hydrolysis, which limits their expression. When O₂ levels are decreased, PHD activity is inhibited and HIF expression is upregulated, prompting a response to counter the effects of reduced O₂. Several HIF and PHD isoforms are differentially expressed between renal cells, promoting a differential hypoxic response [9]. A hallmark of the renal hypoxic response is an increase in systemic erythropoietin (EPO). This hormone is produced in peritubular interstitial fibroblasts expressing PHD2 and stimulates erythropoiesis with the aim of increasing the concentration of O₂ delivered to the kidney. Glomerular cells respond to hypoxia by releasing vascular endothelial growth factor (VEGF). This growth factor mediates the growth and repair of microvessels by stimulating the proliferation of endothelial cells, thereby promoting blood flow. While these responses seem to aim at restoring renal pO₂ levels by increasing [8] supply, cells also manage hypoxic events by limiting O₂ consumption. Adenosine triphosphate (ATP)-dependent membrane carrier activity is reduced and glycolytic enzyme expression is enhanced, thereby preventing oxidative phosphorylation in the mitochondria and favoring non-O₂-mediated anaerobic metabolism to ensure ATP production. These mechanisms, and the fact that they are readily reversed when physiological O₂ levels are restored, illustrate the plasticity of renal cells in response to hypoxia. In addition to the direct role of the PHD-HIF axis in sensing O₂ levels, this mechanism has profound implications for cellular regulation. pHD1 and PHD2 inhibit the activity of the nuclear factor- κ B (NF-kB) pathway, which is involved in cell proliferation and inflammatory responses. pHD3 interacts directly with pyruvate kinase to inhibit glycolytic activity, bypassing HIF activity to some extent. Conversely, the induction of HIF activity is also independent of O₂ levels. Post-transcriptional regulation (e.g. phosphorylation) also plays an important role in recruiting the activity of these factors to meet the different physiological demands under normoxic conditions. HIF has been reported to control the expression of over 500 genes involved in cell growth, energy production, mobility, angiogenesis, cell cycle, and even gene expression itself (chromatin remodeling) [10]. These pathways are essential for maintaining cellular and tissue homeostasis, hence their importance in the hypoxic response.

Hypoxia Response and Renal Pathophysiology

The PHD-HIF axis plays an important role in renal pathophysiology. Kidney cancer and chronic kidney disease (CKD) are two diametrically opposed pathologies; however, at their core is the regulation of PHD-HIF and its associated pathways. Both diseases have major non-genetic risk factors, including age, hypertension, obesity, diabetes, and smoking. Kidney cancer is also a risk factor for renal insufficiency and vice versa. Kidney physiology with low pO2 is vulnerable to hypoxic damage, especially due to conditions that impair the renal blood supply, such as vasoconstriction and vascular injury. The resilient nature of renal cells allows them to adapt and recover extensively from the injury event and restore their physiological function. RPTEC, in particular, are able to guide their physiology through hypoxic conditions, considering their high energy demands. Increasing evidence emphasizes that the malfunction of their stress response mechanisms is the main cause of the development of these renal pathologies (Figure 1).

Figure 1:Cellular response to oxygen levels. (A): Under normal conditions, PHD have access to sufficient oxygen levels to promote the hydroxylation of HIF and maintain a stable expression of these transcription factors. Excess HIF is a target for proteolytic degradation mediated by VHL. (B): When cellular oxygen levels drop below the levels required to ensure PDH activity, HIF expression is destabilized. VHL is precluded from recognizing HIF and a lack of degradation leads to the activation of a myriad of genes with diverse functionalities. HIF activity will ensure cell survival and facilitate the restoration of physiological oxygen levels. Unchecked HIF activity can result in the sustained expression of inflammatory factors. (C): In RCC, the loss of VHL activity leads to the constitutive activation of HIF and predominantly inflammatory and unbalanced cellular activity. (D): The differential activity of HIF in low oxygen conditions or in the absence of VHL leads to the upregulation of several interconnected cellular pathways.

The most common type of kidney cancer is renal cell carcinoma (RCC). rCC originates from RPTEC, differentiates, and acquires a malignant phenotype. Depending on its aggressiveness, RCC can be a rapidly growing invasive tumor. This cancer is characterized by loss of function of the von Hippel-Lindau (VHL) protein [12]. This inactivation may be caused by genetic factors, sporadic mutations, or epigenetic modifications (e.g., DNA methylation), the end result of which is the constitutive activation of HIF. VHL recognizes hydroxylated HIF and promotes the activity of the E3 ubiquitin ligase complex, which then mediates the hydrolytic degradation of HIF proteins via ubiquitination. By removing VHL from this mechanism, HIF expression becomes stable and is no longer repressed, leading to the deregulation of its target genes [13]. The balance between VHL repression and HIF activity is a major determinant of RCC pathogenesis, progression, and outcome. Two HIF variants, -1α and -2α, are recognized by VHL and are specifically associated with clear cell RCC (ccRCC), the most common RCC subtype. In the kidney, HIF-1α is predominantly expressed in tubular cells, whereas HIF-2α is present in glomerular cells, fibroblasts, and endothelial cells. In RPTEC, HIF-1α is key in regulating baseline glycolysis and cell cycle, acting as a tumor suppressor gene in this way. With the development of a malignant phenotype, cells acquire expression of HIF-2α, which is otherwise absent. hIF-2α is key to tumorigenic activity, upregulating proliferation, angiogenesis, and mediating inflammatory responses [14]. As cancer cells further differentiate, HIF-1α expression may be completely lost and HIF-2α exerts its regulatory activity.RCC is a highly glycolytic and angiogenic tumor that overexpresses glycosyl membrane transporter proteins and VEGF to meet its anaerobic metabolism [15].

Epidemiological studies have shown direct and indirect interdependent associations between CKD and the development of genitourinary cancers. Early renal insufficiency is not associated with cancer development, but cancer incidence is 10 - 20 times higher in patients with advanced CKD. It is known that this stems from the systemic accumulation of toxic metabolites and eventually the accumulation of drugs after the decline of renal function, a factor that leads to cytotoxicity and impaired immune response [16]. On the other hand, due to the cytotoxicity and renal excretion of several chemotherapeutic drugs, renal damage can be caused. The latest generation of anticancer drugs (e.g., tyrosine kinase inhibitors, biopharmaceuticals) have greatly reduced the nephrotoxic effects and overcome the chemically induced renal damage associated with previous generations of drugs, as exemplified by cisplatin. Partial nephrectomy, a surgical procedure to remove RCC tumors, usually requires clamping of the renal vasculature, effectively blocking blood flow. Medically induced ischemia can also lead to renal hypoxic injury. there is a positive correlation between RCC diagnosis and CKD, however, any underlying mechanisms linking these two pathologies remain largely unknown.

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While the role of the PDH-VHL-HIF axis in RCC is well characterized, its effects and the role of hypoxia in CKD are far more elusive. CKD is a complex, multifactorial, insidious disease characterized by the loss of whole kidney function. Over time, without proper clinical management, it often leads to renal failure. In contrast to RCC, this pathology actually affects all cell types in the renal unit, not only RPTEC. The effects of hypoxia in CKD are traditionally thought to adversely damage the renal capillary network [18]. Restricted blood flow leads to a chain reaction in which hypoxic renal cells promote fear in the peritubular space and cause irreparable damage to the kidney and the vascular system. This damage stems from renal fibrosis, one of the most important factors contributing to the pathophysiology of CKD, characterized by the deposition of extracellular matrix (ECM) proteins in the peritubular space. In a hypoxic environment, RPTEC turnover is impaired and epithelial cell aging leads to tubular loss and degeneration of renal function [19]. The conflicting activities of HIF-1α described in a large number of comprehensive studies challenge the understanding of the effects of CDK hypoxia. On the one hand, HIF-1α activity promotes the recovery of damaged tubule cells by controlling their dedifferentiation and growth, inhibiting inflammation, and fibrosis, and improving renal function. On the other hand, HIF-1α appears to promote the opposite, increasing fibrosis and accelerating tubular and glomerular injury. Interestingly, most deleterious effects were observed in studies involving HIF-1α overexpression or knockdown, while most positive effects were observed in studies using pharmacological interventions. This evidence was elaborated by Faivre et al [20] and the experimental model used may be an important factor in the reported HIF-1α activity.

Nevertheless, these dual effects suggest that the post-transcriptional regulation of HIF-1α, rather than its expression, determines its physiological impact. Dedifferentiated renal epithelial cells acquire a profibrotic phenotype and drive tubulointerstitial inflammation [8]. HIF-1α appears to drive regeneration and epithelial-to-mesenchymal transition (EMT), contributing to the proliferation of differentiated RPTEC that do not fully recover their epithelial phenotype. The deposition of extracellular matrix by these profibrotic cells can exacerbate functional loss by promoting tissue fibrosis [21]. In a similar manner, mesenchymal fibroblasts, in the peritubular space, can proliferate and deposit ECM when driving predominantly anaerobic metabolism. This process is mediated independently by hypoxia, and transforming growth factor beta (TGF-β), a cytokine that controls cell proliferation, inhibits the activity of PHD2, leading to an imbalance in HIF expression [22]. The role of inflammation as another hypoxia-independent activator of HIF in pathophysiological conditions is emerging, with different regulatory pathways interacting with HIF. Tumor necrosis factor α (TNF-α), a cytokine released by macrophages in response to cellular stress, can indirectly stabilize the cellular levels of HIF-1α through the transcriptional activity of NF-kB.

Common Traits in RCC and CKD

In contrast to RCC, there is no evidence that VHL expression and activity are impaired during the pathogenesis and progression of CKD. This supports the fact that the key difference between the two pathologies is that HIF activity does not remain completely unsuppressed during CKD. rCC, especially in advanced stages, is a highly inflammatory tumor. rCC releases a series of cytokines that are thought to contribute to the maintenance of its microenvironment and the self-regulation of the cancer phenotype. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) play important roles in tumor proliferation by regulating cell growth and metabolism. Recently, systemic inflammation has been considered a marker of RCC progression [23]. The secretion of cancer-specific cytokines and chemokines enables advanced RCC to isolate the activity of immune cells and promote a metastatic cascade leading to the spread and engraftment of cancer cells outside the primary tumor [24]. The inflammatory nature of RCC can be considered a mechanism of cancer survival and proliferation, with a clear impact on systemic inflammation. Intra-tumor fibrosis (ITF) is the result of a complex interaction between cancer and infiltrating cells, leading to the accumulation of dense ECM deposits in the primary tumor and playing an important role in maintaining the cancer microenvironment and as a reservoir of immune cells [25]. Indirect evidence suggests that ITF is associated with the development of RCC as an invasive tumor with poor clinical prognosis; however, little is known to date about the role of ITF in the pathophysiology of renal cell carcinoma. The same mechanisms associated with renal fibrosis (e.g., TGF-β, EMT) are also present in ITF tissue, and a better understanding of the significant fibrosis at the onset of RCC could elucidate the common causes of both diseases before they evolve and develop their intrinsic phenotypes. In addition, the impact of inflammation and ITF on normal renal physiology is uncertain.

Cistanche tubulosa benefits

why does Cistanche extract benefit the Kidneys?

As a valuable herb, Cistanche contains many compounds that are beneficial to the human kidney. It contains phenylethanoid glycosides, Echinacoside, and Verbascoside. These components can help increase the proliferation rate of kidney cells by 8 to 10 times, inhibit the apoptosis of kidney cells, and improve the repair of damaged kidney cells.

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3.martin.burchardt@med.uni-greifswald.de (M.B.)

* Correspondence: ingmar.wolff@med.uni-greifswald.de