Sirtuins In Kidney Health And DiseaseⅣ

acute kidney injury

Regardless of the initial injury, dysfunction, and loss of tubular epithelial cells play a key role in the evolution of acute kidney injury (AKI). In this context, mitochondrial dysfunction has been identified as the earliest pathological sign preceding tubular cell loss. Consistent with this observation, accumulating evidence suggests that SIRT1 has a protective role in AKI. Renal tubular cell-specific overexpression of SIRT1 is sufficient to protect against cisplatin-induced AKI in mice. In the ischemia–reperfusion injury (IRI) model of AKI, SIRT1-dependent deacetylation of PGC1α is required to promote mitochondrial biogenesis and oxidative respiration. Maintain energy supply for canalicular repair after injury. Consistent with this result, SIRT1 silencing significantly aggravated renal IRI. The ability of SIRT1 to protect the kidney from injury is also attributed to its role in suppressing the inflammatory response of renal tubular epithelial cells by targeting the NF-κB and Nrf2 pathways. These findings provide a theoretical basis for the use of SIRT1 activators to prevent AKI, including flavonoids, AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), and Resveratrol.

Click to Cistanche for kidney disease

SIRT6 overexpression has been shown to attenuate cisplatin-induced renal injury. SIRT6 inhibits the expression of ERK1 and ERK2 by deacetylating histone H3K9, thereby inhibiting inflammation and apoptosis. Of potential clinical significance, SIRT6 is expressed in the injured kidneys of female but not male mice, suggesting that SIRT6 may be a molecular determinant of female protection in AKI.

Since altered mitochondrial homeostasis predominates in AKI, the role of mitochondrial SIRTs, especially SIRT3, is a very interesting topic. In the cisplatin-induced AKI mouse model, decreased renal SIRT3 protein expression was associated with the accumulation of oxidative stress markers and increased mitochondrial fission resulting from Opa1 hyperacetylation and downregulation. SIRT3 has been shown to regulate the expression of Opa1 through deacetylation and inactivation of ATP-dependent zinc metalloprotease YME1L1, accelerating Opa1 cleavage, and leading to mitochondrial network fragmentation. Similarly, SIRT3 preserves Mfn2 ubiquitination and degradation in renal IRI. These data suggest that an imbalance in mitochondrial dynamics toward fragmentation caused by SIRT3 deficiency is a unifying feature in various experimental models of AKI, leading to mitochondrial permeability, ATP depletion, ROS overproduction, and apoptotic factor release. The non-redundant role of SIRT3 in AKI was confirmed as SIRT3-deficient mice exhibited more severe disease and premature death after cisplatin administration compared with wild-type mice. The outcome of these studies is that SIRT3 is a potential target for pharmacological intervention to alleviate AKI. AICAR can restore the expression and activity of SIRT3 in wild-type mice, improve renal function, and reduce renal tubular damage, but it has no such effect in SIRT3 knockout mice. Other potential SIRT3 activators, such as curcumin, flavonoids, resveratrol, silibinin, and stannocalcin also have protective effects against experimental AKI.

An alternative strategy to restore and activate SIRT3 is NAD+ supplementation. In mouse models, supplementation with the NAD+ precursors nicotinamide mononucleotide (NAMN) and nicotinamide riboside (NR) has a protective effect on AKI. NAD+ bioavailability is significantly reduced when cisplatin induces AKI in renal tubular epithelial cells, thereby negatively affecting SIRT3 activity. Co-incubation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) with cisplatin-damaged renal tubular cells induces the upregulation of several key enzymes in the NAD+ biosynthetic pathway, including those that play a role in the rescue pathway Nicotinamide phosphoribosyltransferase (NAMPT) and kynureninase function in the de novo pathway (Figure 2c). The upregulation of these enzymes was accompanied by the restoration of NAD+ levels and SIRT3 activity in the kidney tissue of cisplatin-treated mice. The researchers also found that UC-MSCs enhanced SIRT3 activity, allowing healthy mitochondria to undergo intercellular transfer between tubular epithelial cells through tubulin-rich projections, which facilitated bioenergetic crosstalk between damaged tubular cells. These effects translate into protective effects of UC-MSCs on renal function and mitochondrial homeostasis in AKI mice through NAMPT and PGC1α upregulation of SIRT3. In contrast to the protective effects of other SIRTs, two mouse studies have shown that SIRT7 has a deleterious role in the process of AKI, but the pathological mechanism is not yet clear.

In contrast, SIRT1 promotes autoantibody production and cyst formation in autoimmune kidney disease and polycystic kidney disease, while SIRT7 induces inflammatory responses in acute kidney injury.

Little is known about the role of SIRTs in patients with AKI. However, NAD biosynthesis has been reported to be impaired in hospitalized patients at high risk for AKI. This finding suggests that using treatments that increase NAD+ levels, similar to those studied in experimental models, maybe a valuable kidney-protective strategy for patients with AKI.

diabetic nephropathy

Diabetic kidney disease (DKD) is the leading cause of renal failure worldwide and is also a risk factor for cardiovascular disease. SIRTs have been extensively studied in DKD due to their prominent role in regulating cellular metabolism.

SIRT1 agonists can improve metabolic parameters such as glucose tolerance and insulin resistance and extend the survival time of diabetic animals. In addition to these positive metabolic effects, SIRT1 directly limits podocyte damage. In DKD mice, conditional podocyte deletion of SIRT1 increases proteinuria and worsens renal damage. The protective effect of SIRT1 is associated with increased acetylation of STAT3 and NF-κB p65 subunits in podocytes. In addition, reduced SIRT1 expression can lead to glomerular FOXO4 hyperacetylation and induction of pro-apoptotic factors in DKD mice. Short-term application of the NAD+ precursor NAMN achieved renal protection through the upregulation of SIRT1 and NAD+ rescue pathways in early DKD mouse models. Consistent with this evidence, SIRT1 is downregulated in glomeruli of patients with diabetes, and dietary intervention aimed at increasing SIRT1 reduced levels of advanced glycation end products and restored antioxidant defenses in patients with DKD.

Diabetic mice have reduced SIRT6 expression and AMPK dephosphorylation levels, accompanied by abnormal mitochondrial morphology and progressive renal damage. In high glucose-exposed rat mesangial cells, an in vitro model of DKD, SIRT6 is downregulated by a miR-33a-5p-dependent pathway. In streptozotocin (STZ)-induced diabetic mice, circRNA E3 ubiquitin-protein ligase (circRNA circ ITCH) improves renal inflammation and fibrosis by inhibiting miR-33a-5p and thereby increasing SIRT6 expression. SIRT6 regulates fibrosis by directly binding to and deacetylating Smad3, preventing its nuclear accumulation and transcriptional activity of genes related to epithelial-to-mesenchymal transition and renal fibrosis. In STZ-induced diabetic mice, tubular cell-specific deletion of SIRT6 enhanced the fibrotic phenotype by increasing matrix metalloproteinase Timp1 expression and extracellular matrix deposition. SIRT6 overexpression also protected STZ-induced podocyte damage in DKD rats by polarizing macrophages to a protective M2 phenotype and limiting interleukin and cytokine production. It is suggested that SIRT6 plays a role in regulating immune response and protecting kidneys from inflammatory damage in DKD. The expression of SIRT6 is also inhibited in podocytes of DKD patients.

SIRT3 also has a protective role in DKD. Overexpression of SIRT3 in renal tubular cells inhibits the accumulation of ROS by upregulating the Akt–FoxO signaling pathway, thereby resisting hyperglycemia-mediated renal cell apoptosis. SIRT3 expression is reduced in the kidneys of mice and DKD patients. Honokiol can selectively activate SIRT3, reduce proteinuria, and improve glomerular damage in diabetic mouse models (BTBR ob/ob mice). This renoprotective effect relies on honokiol-induced SIRT3 activation, which protects mitochondrial function and ultrastructure by activating SOD2 and restoring glomerular cell PGC1α expression.

On the other hand, lack of Sirt3 increases the severity of high-fat diet-induced kidney disease in mice, a condition similar to metabolic syndrome in humans. In this case, Sirt3 deficiency leads to lipid accumulation and mitochondrial damage in renal tubular cells. Ectopic lipid accumulation in the renal tubules is a significant pathological feature of DKD patients, which occurs due to reduced levels of the hormone meteorite-like protein (Metrnl) produced by skeletal muscle and adipose tissue. Metrnl can activate the SIRT3-AMPK signaling axis, maintain mitochondrial homeostasis, promote thermogenesis, and thereby reduce lipid accumulation. Application of recombinant Metrnl can reduce lipid accumulation and improve kidney damage in diabetic mice, suggesting that SIRT3 can delay the progression of DKD through a new mechanism.

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, is 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.