Complete Interpretation Of HIF-PHI Mechanism

Chronic kidney disease (CKD) has become a major chronic disease that harms China and the world. The latest data shows that the number of CKD patients in China exceeds 82 million [1]. As a common clinical manifestation of kidney disease patients, anemia is not only an important complication of kidney disease but also a common comorbid disease. Its occurrence and development seriously affect the health of kidney disease patients. Quality of life also promotes the progression of kidney disease and increases the risk of cardiovascular events and death [2].

Click to Cistanche for kidney disease

In the past, erythropoiesis-stimulating agents (ESA) and iron were mainly used clinically to treat renal anemia. However, the hemoglobin compliance rate of patients is still low, and there is an urgent need to develop more effective and convenient drugs in clinical practice. In recent years, the successful development of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) has brought a new direction to the field of innovative therapeutic drugs for global renal anemia after 30 years and opened up a new era of anemia treatment for CKD patients. era.

The situation is grim and standardized treatment needs to be improved

Renal anemia refers to anemia caused by various kidney diseases that lead to absolute or relative insufficient production of erythropoietin (EPO), and uremic toxins that affect the production and lifespan of red blood cells. For a long time, the incidence of anemia in CKD patients in my country has been significantly higher than that in the general population. As the renal function of patients declines, the prevalence of renal anemia increases, and the degree of anemia also worsens. The overall prevalence of anemia in non-dialysis CKD patients in my country is The rate is 28.5%-72.0%, and the prevalence of anemia in dialysis patients is even as high as 91.6%-98.2%[2].

Although the number of anemia patients remains high, the clinical diagnosis and treatment status of renal anemia in China is still not optimistic. According to the "Clinical Practice Guidelines for the Diagnosis and Treatment of Renal Anemia in China" [2], the target hemoglobin (Hb) for patient treatment is Hb ≥ 110g/L, but not more than 130g/L. However, the results of a 2016 study [3] showed that among 2420 non-dialysis Chinese CKD patients, only 39.8% of the anemic patients received EPO treatment, and 27.1% of the patients received iron therapy. After treatment, the Hb reached 110~120 g/ Only 8.2% of patients were L, which shows that there is still great room for improvement in the diagnosis and treatment of renal anemia in China.

The reason for this clinical dilemma may be that on the one hand, clinicians have insufficient systematic assessment of renal anemia and unreasonable drug use. On the other hand, traditional therapeutic drugs also have certain limitations, such as the poor absorption and utilization of oral iron. Low, long-term response rate and target rate are insufficient [12,13]; the use of high-dose ESA may lead to increased blood pressure, stroke, and increased risk of tumor progression, and the higher the dose, the higher the risk [14].

Therefore, standardizing the diagnosis and treatment of renal anemia and promoting rational medication use in patients with renal anemia is crucial to improving the clinical status. In addition, ESA and iron therapy, as traditional clinical treatments for renal anemia, cannot comprehensively regulate the multiple pathways of renal anemia. The development of drugs with innovative mechanisms that can effectively and conveniently treat renal anemia is also an urgent clinical issue. question.

Nobel Prize Mechanism, Full Interpretation of HIF Pathway

Hypoxia-inducible factor (HIF) is not new to the academic community. As early as the 1990s [15], HIF had been discovered in hypoxic liver cancer cells. In 2019, three scientists were awarded the Nobel Prize in Physiology or Medicine for their outstanding contributions in discovering and elucidating "cellular oxygen sensing and adaptation."

As a key dimeric complex transcription factor in the human body involved in cell regulation and oxygen transport efficiency, HIF is composed of α subunit (HIF-α) and β subunit (HIF-β) [16]. It induces target cells by activating downstream signaling pathways. Gene expression, including erythropoiesis, angiogenesis processes, etc. HIF widely exists in the body under hypoxic conditions and maintains the homeostasis of the body's internal environment. It has important biological significance in physiological and pathophysiological processes such as tumors, anemia, inflammatory response, cardiac and cerebral ischemia, and embryonic development.

Scholars have found that HIF-1 initiates gene expression in a hypoxic environment, and when cells transition to hyperoxic conditions, the amount of HIF-1 drops sharply (see Figure 2). This is because, in a normoxic environment, the tumor suppressor gene protein common in Hippel-Lindau syndrome (VHL) binds to HIF-1α, a component of HIF, and directs its ubiquitination and degradation [17]. Further research found that in a normoxic environment, an oxygen atom will combine with a hydrogen atom of proline with the participation of prolyl hydroxylase (PHD) to form a hydroxyl group. Once this proline is removed, HIF- The ubiquitination of 1α will be inhibited [18].

Under hypoxic conditions, the activity of PHD will be inhibited, increasing the level of HIF-1α and promoting the up-regulation of EPO and other related factors. Scientists have found that HIF-PHI drugs can simulate the physiological response of the body during hypoxia, inhibit PHD activity, stabilize HIF levels, rapidly and reversibly induce the upregulation of HIF-α expression, and promote the formation of stable dimers between HIF-α and HIF-β. , activates HIF and induces target gene expression, promotes endogenous EPO production, upregulates EPO receptor expression, promotes duodenal iron absorption, improves iron absorption and utilization, effectively promotes erythropoiesis, and thereby improves anemia.

Research supports that HIF activation may be beneficial

There are also previous observational studies [20] that compared the outcomes of CKD patients in high-altitude areas and low-altitude areas, and evaluated the anemia outcomes of CKD patients in four altitude categories, including the utilization rate of ESA and iron supplements, and the proportion of patients using them.

The results of the study found that compared with low-altitude areas (0-1499 feet above sea level), the proportion of patients receiving ESA and iron therapy in high-altitude areas (elevation ≥4500 feet) decreased by 13.9% and 10.1% respectively, and the average number of patients in high-altitude areas Hb levels were higher; in terms of drug dosage, patients at high altitudes used lower doses of ESA, while there was no significant difference in the dosage of iron. This result suggests that despite lower ESA use in patients at high altitudes, the higher Hb they achieve is not due to increased intravenous iron therapy.

It is worth mentioning that the researchers found a monotonically increasing relationship between higher altitude and lower incidence of ESA hyporesponse. The incidence of ESA hyporesponse in patients at high altitudes was nearly 50% lower than that in patients at lower altitudes (3.5% vs. 7.6%), correspondingly, the mean and median EPO resistance index (ERI) gradually decreased with increasing altitude.

The researchers suggest that the improved anemia treatment outcomes in patients at higher altitudes and in those at lower altitudes may be due to the potential beneficial effects of HIF activation at high altitudes. HIF activation endogenously increases EPO synthesis by mobilizing iron from storage pools, thereby reducing the need for anemia medications in the study's patients living at high altitudes.

summary

The standardized diagnosis and treatment of renal anemia in China has always been a major clinical issue that needs to be solved urgently. However, the occurrence of renal anemia is driven by multiple factors. Simply supplementing ESA and/or iron cannot comprehensively regulate and solve various problems. HIF-PHI, which has multiple mechanisms, can endogenously promote the production of physiological concentrations of EPO, induce erythropoiesis, and maintain EPO levels [21]. Currently, it has been recommended by multiple guidelines/consensus for the treatment of renal anemia [2,21 , twenty-two]. We believe that the advent and standardized clinical use of HIF-PHI innovative drugs can bring new choices and benefits to patients with renal anemia!

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammation mandatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.