Sirtuins In Kidney Health And DiseaseⅡ

Sirtuins in mammalian physiology

Initial studies of SIRTs have focused on identifying specific substrates for their enzymatic activity, to reveal their unique contributions to various cellular processes. As the understanding of SIRTs continues to evolve, emerging paradigms suggest that SIRTs regulate functional clusters of target proteins, orchestrating finely tuned physiological responses across multiple cellular processes, including metabolic regulation, oxidative stress, cell survival, and maintenance of genome stability. sex. Their involvement in multifaceted biological pathways establishes SIRTs as key regulators of cellular homeostasis.

Click to Cistanche for kidney disease

metabolic regulation

SIRT initially attracted attention for its beneficial effects in modulating caloric restriction, the only physiological intervention to extend lifespan in various experimental models. In-depth studies have elucidated the network of SIRT regulatory proteins that control energy homeostasis, showing that all SIRTs regulate cellular metabolism to varying degrees.

The potential role of SIRT3 in cellular metabolism has received widespread attention due to its prominent mitochondrial localization. In particular, SIRT3 was found to regulate the deacetylation and transcription of multiple targets within the electron transport chain (ETC) complex through deacetylation of mitochondrial ribosomal protein 10 (MRPL10). SIRT3 coordinates metabolic homeostasis by stimulating fatty acid β-oxidation and ketone body production. Nuclear SIRTs also play a role in metabolic regulation. SIRT1 regulates the activity of transcription factors, including peroxisome proliferator-activated receptor-γ (PPARγ), peroxisome proliferator-activated receptor-γ coactivator 1-α (peroxisome proliferator-activated receptor gamma coactivator 1-α, PGC-1α) and forkhead box type O transcription factors (FOXO), which regulate multiple pathways, including lipid metabolism, glucose homeostasis, and Gluconeogenesis. SIRT6 inhibits the transcriptional activity of hypoxia-inducible factor 1α (HIF-1α) through the deacetylation of H3K9 in the HIF-1α promoter, thereby inhibiting the expression of glycolysis genes and thus serving as a major regulator of glucose homeostasis. regulating factors. This mechanism enables SIRT6 to maintain efficient glucose flow into the TCA cycle under normal nutritional conditions. Deletion of SIRT6 in myeloid cells predisposes mice to glucose intolerance and insulin resistance.

Mitochondrial dynamics and biogenesis

Mitochondria are ubiquitous organelles, but their morphology and number vary widely among tissues and change rapidly with the supply of nutrients. Mitochondria exist in dynamic networks whose morphology is determined by the opposing events of fission and fusion (Fig. 3b), tightly controlled to regulate energy output.

Fission causes mitochondria to divide, producing smaller mitochondria, thereby increasing the overall mass of the organelle and allowing a rapid increase in energy supply. However, smaller mitochondria have increased susceptibility to membrane depolarization and oxidative damage. The molecular mechanism of division includes the recruitment of cytoplasmic dynamin-related protein 1 (Drp1) to the outer mitochondrial membrane. Drp1 binds to the mitochondrial fission factor (Mff), and the resulting complex forms a ring-like structure around the mitochondria, severing the organelle.

In contrast, fusion induces an interconnected mitochondrial network that dilutes the toxic effects of reactive oxygen species (ROS) generated during normal metabolism and favors sustained energy production. Fusion occurs through the self-assembly of GTPases, namely mitochondrial fusion proteins (Mfn1 and Mfn2) and optic atrophy 1 (Opa1), on the inner and outer mitochondrial membranes. SIRT1 and SIRT3 promote mitochondrial fusion by directly deacetylating Mfn2 and Opa1 respectively, while SIRT6 promotes mitochondrial fusion by preventing Drp1 phosphorylation through Rho-associated protein kinase 1 (ROCK1).

The number of mitochondria within a cell also depends on the opposite processes of biogenesis and mitophagy. Mitochondrial biogenesis is the rebirth of new mitochondria and is mainly controlled by PGC1α. SIRT1 can regulate mitochondrial biogenesis by directly deacetylating PGC1α, while SIRT6 can indirectly induce deacetylation of PGC1α. SIRT3 induces PGC1α expression in an AMP-activated protein kinase (AMPK)-dependent manner, thereby promoting mitochondrial biogenesis.

Mitophagy is a quality control process that separates damaged mitochondria from healthy networks for disposal. SIRT1 and SIRT3 can directly induce the serine/threonine kinase PTEN-induced putative kinase 1 (PINK1)-Parkin-dependent mitotic phagocytosis, and indirectly through mechanisms such as FOXO1/3 deacetylation. SIRT1 also reduces the Expression of the mammalian target of rapamycin (mTOR) and induces mitochondrial phagocytosis. SIRT3 indirectly enhances mitochondrial phagocytosis by activating AMPK and increasing mitochondrial membrane potential. To date, the role of SIRT6 in mitophagy has not been reported.

oxidative stress

Enzymes and subcellular compartments related to metabolic regulation are often the largest producers of ROS, which are ultimately cleared by the endogenous antioxidant system. Oxidative damage occurs when ROS production exceeds the scavenging capacity of cellular antioxidant enzymes and plays a key role in triggering multiple pathogenic conditions in different organs.

SIRTs work synergistically to rapidly sense and enhance intracellular antioxidant defense (Figure 3c). SIRT1 and SIRT6 can activate the separation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) from the inhibitory protein Keap1, inducing the expression of antioxidant genes. Furthermore, SIRT1 and SIRT3 activate several FOXO family members involved in regulating oxidative stress. FOXO1 can clear excess ROS by regulating downstream target genes such as superoxide dismutase 2 (SOD2) and catalase. In addition, SIRT1, SIRT3, and SIRT6 are deacetylated, thereby inhibiting the activation of the transcription factor NF-κB. This mechanism limits the upregulation of pro-oxidative genes that promote ROS production.

Mitochondria, the site of oxidative phosphorylation, are the main cellular source of ROS and are particularly susceptible to ROS-induced damage. Mitochondrial SIRTs promote the activation of specific enzymes involved in ROS clearance. In particular, the SIRT3 deacetylase SOD2 facilitates the scavenging of superoxide and isocitrate dehydrogenase 2, which promotes the regeneration of antioxidants and catalyzes key regulatory points in the tricarboxylic acid (TCA) cycle.

DNA damage and apoptosis

When the antioxidant detoxification system cannot maintain ROS at a tolerable level, an excessive intracellular pro-oxidative environment can trigger extensive and irreparable DNA damage, including base modifications, DNA cross-links, and single- or double-strand breaks. ultimately promote cell death. Nuclear SIRT has a protective role in protecting DNA from damage. Spatiotemporal regulation of DNA repair by SIRT1 and SIRT6. SIRT1 deacetylation of SIRT6 at K33 precedes SIRT6 polymerization and recognition of double-stranded DNA breaks, resulting in localized chromatin remodeling. Furthermore, SIRT1 antagonizes DNA strand breaks through Ku70 deacetylation.

SIRT also has multifaceted roles in apoptosis protection. In mesangial cells, SIRT1 inhibits apoptosis by activating p53 and Smad7. SIRT1 also reduces glomerular podocyte apoptosis through FOXO4-dependent inhibition of Bim, a key determinant in initiating the intrinsic apoptotic pathway. SIRT3 exerts anti-apoptotic effects by controlling ROS accumulation, while SIRT6 protects cells from apoptosis by regulating Notch signaling and the actin cytoskeleton.

Autophagy 

Autophagy is a tightly regulated process that allows the disposal of abnormally modified proteins, aggregates, and damaged organelles through lysosomal degradation, thereby protecting cells from apoptosis. SIRTs participate in the regulation of the autophagy process by directly deacetylating essential proteins of the autophagy mechanism as well as through indirect mechanisms.

Starvation activates SIRT1, which in turn deacetylates autophagy components, including Atg5, Atg7, and LC3. SIRT1 also activates autophagy through the deacetylation of Mfn2 in mitochondria. Existing data indicate that SIRT3 and SIRT6 can regulate autophagy by activating multiple downstream signaling pathways. SIRT3 increases the expression of Beclin-1 and LC3II in renal tubular cells by downregulating the Notch-1–Hes-1 pathway, thereby promoting autophagy and the ERK–CREB signaling pathway. Similarly, SIRT6 overexpression induces autophagy by attenuating the insulin-like growth factor (IGF)-Akt-mTOR signaling pathway; however, its molecular mechanism requires further study.

cellular senescence

Cellular senescence is a stable form of cell cycle arrest that is induced by telomere shortening during temporal aging and by multiple endogenous and exogenous stimuli. Senescence is a dynamic, multistep process in which cells undergo substantial changes in gene expression, become unresponsive to growth-promoting signals, and develop a complex senescence-associated secretory phenotype (SASP). Although there is still controversy, increasing evidence shows that SIRT alleviates cellular aging mainly through epigenetic regulation of gene transcription, promotion of autophagy, and enhancement of DNA damage repair.

SIRT1 can maintain H3K9 and H4K16 acetylation, thereby inhibiting the expression of SASP pro-inflammatory components IL-6 and IL-8. In addition, SIRT1 antagonizes cellular senescence by fine-tuning the ERK signaling pathway and regulating the deacetylation of LKB1 and its downstream target protein AMPK. SIRT6 binds to telomeres, and inhibition of SIRT6 can induce telomere damage and senescence, which is related to telomeric H3K9 hyperacetylation and p53-binding protein 1 (53BP1) binding. In addition, SIRT6 limits cell cycle arrest through proteasomal degradation of p27Kip1, a member of the cell cycle-dependent kinase inhibitor family, thereby delaying senescence. SIRT3 ultimately stabilizes heterochromatin by interacting with nuclear envelope proteins and heterochromatin-related proteins, thereby resisting aging, alleviating oxidative stress, and promoting autophagy.

Inflammation and immune response

An emerging concept in bioenergetics is the continuum of cellular metabolism with the recruitment and activation of immune cells and inflammation. Although research on the role of SIRT in inflammation is still in its early stages, increasing evidence suggests that NAD+ levels and SIRT transcript and/or protein levels are continuously reduced in specific tissues during chronic inflammation. The ability to inhibit NF-κB activation gives SIRT1 strong anti-inflammatory activity in several cell types. SIRT1 also regulates inflammation through deacetylation of high-mobility group box 1 (HMGB1). It is a highly conserved non-histone structural protein that is usually located in the nucleus and maintains the structure and function of chromosomes. Loss of SIRT1 increases HMGB1 acetylation and release into the extracellular space, inducing signaling cascades leading to systemic inflammation. Activation of SIRT1 and SIRT3 also has anti-inflammatory effects, such as reducing tumor necrosis factor (TNF) production by macrophages and monocytes during acute inflammation. Myeloid cell-specific deletion of SIRT1 exacerbates organ dysfunction and mortality in experimental models of systemic inflammation. SIRT3 reduces inflammation by regulating the NLRP3 inflammasome, thereby inhibiting oxidative stress and pro-inflammatory cytokines. In a kidney stone mouse model, SIRT3 gene knockout resulted in a decrease in resident B cells in the kidney and an increase in macrophage and granulocyte infiltration, suggesting that SIRT3 expression affects the immune cell landscape in the tissue.

A 2023 study identified mechanisms by which mitochondrial disturbances are linked to inflammation during kidney injury. Researchers found that cytoplasmic leakage of mitochondrial RNA (mtRNA) and activation of the cytoplasmic pattern recognition receptor retinoic-inducible gene 1 protein (RIG1, also known as DDX58) lead to inflammatory cell organization recruitment. RIG1-like receptors are key sensors of viral or bacterial infection, and activation of RIG1-dependent cytoplasmic RNA sensing pathways can induce a pro-inflammatory state. The ability of mtRNA to induce activation of this pro-inflammatory signaling pathway may be the result of the endosymbiotic origin of mitochondria, which evolved from bacteria and share conserved structural motifs with prokaryotes. Supplementing NAD+ precursors can restore NAD+ levels, improve mitochondrial function, and prevent kidney damage. This finding suggests that SIRTs, specifically SIRT3, may play a protective role by maintaining mitochondrial integrity and preventing mitochondrial RNA leakage.

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.