Potent efficacy of Stachybotrys microspora triprenyl phenol-7, a small molecule having anti-inflammatory and antioxidant activities, in a mouse model of acute kidney injury.

Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD), complicates existing CKD, and can lead to the end-stage renal disease. However, there are no approved effective therapeutics for AKI. Recent studies have suggested that inflammation and oxidative stress are the primary causes of AKI. We previously reported the potential anti-inflammatory and antioxidant activities of Stachybotrys microspora triprenyl phenol-7 (SMTP-7). The aim of the present study was to evaluate the efficacy of SMTP-7 in AKI model mice. AKI was induced in mice by ischemia of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the removal of right kidney. The efficacy of SMTP-7 was determined by measuring the renal function using urine and serum samples and morphological assessment. For deciphering the mechanism of action of SMTP-7, inflammatory cytokines and oxidative stress in kidney were detected. SMTP-7 (0.01, 0.1, 1, 10 mg/kg) dose-dependently improved the renal function. In addition, it improved the damage to renal tubules and exhibited anti-inflammatory and antioxidant activities in the kidney of AKI mice. These results indicate the potential of SMTP-7 as a medicinal compound for the treatment of AKI.

Toll-like receptor 4: An attractive therapeutic target for acute kidney injury.

Acute kidney injury (AKI) is a progressive renal complication which significantly affects the patient's life with huge economic burden. Untreated acute kidney injury eventually progresses to a chronic form and end-stage renal disease. Although significant breakthroughs have been made in recent years, there are still no effective pharmacological therapies for the treatment of acute kidney injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response plays a pivotal role in the pathogenesis of acute kidney injury. The expression of TLR4 has been seen in resident renal cells, including podocytes, mesangial cells, tubular epithelial cells and endothelial cells. Activation of TLR4 signaling regulates the transcription of numerous pro-inflammatory cytokines and chemokines, resulting in renal inflammation. Therefore, targeting TLR4 and its downstream effectors could serve as an effective therapeutic intervention to prevent renal inflammation and subsequent kidney damage. For the first time, this review summarizes the literature on acute kidney injury from the perspective of TLR4 from year 2010 to 2020. In the current review, the role of TLR4 signaling pathway in AKI with preclinical evidence is discussed. Furthermore, we have highlighted several compounds of natural and synthetic origin, which have the potential to avert the renal TLR4 signaling in preclinical AKI models and have shown protection against AKI. This scientific review provides new ideas for targeting TLR4 in the treatment of AKI and provides strategies for the drug development against AKI.

Effective Nephroprotection Against Acute Kidney Injury with a Star-Shaped Polyglutamate-Curcuminoid Conjugate.

The lack of effective pharmacological treatments for acute kidney injury (AKI) remains a significant public health problem. Given the involvement of apoptosis and regulated necrosis in the initiation and progression of AKI, the inhibition of cell death may contribute to AKI prevention/recovery. Curcuminoids are a family of plant polyphenols that exhibit attractive biological properties that make them potentially suitable for AKI treatment. Now, in cultured tubular cells, we demonstrated that a crosslinked self-assembled star-shaped polyglutamate (PGA) conjugate of bisdemethoxycurcumin (St-PGA-CL-BDMC) inhibits apoptosis and necroptosis induced by Tweak/TNFα/IFNγ alone or concomitant to caspase inhibition. St-PGA-CL-BDMC also reduced NF-κB activation and subsequent gene transcription. In vivo, St-PGA-CL-BDMC prevented renal cell loss and preserved renal function in mice with folic acid-induced AKI. Mechanistically, St-PGA-CL-BDMC inhibited AKI-induced apoptosis and expression of ferroptosis markers and also decreased the kidney expression of genes involved in tubular damage and inflammation, while preserving the kidney expression of the protective factor, Klotho. Thus, due to renal accumulation and attractive pharmacological properties, the application of PGA-based therapeutics may improve nephroprotective properties of current AKI treatments.

5-O-methyldihydroquercetin and cilicicone B isolated from Spina Gleditsiae ameliorate lipopolysaccharide-induced acute kidney injury in mice by inhibiting inflammation and oxidative stress via the TLR4/MyD88/TRIF/NLRP3 signaling pathway.

OBJECTIVE: Inflammation and oxidative stress are the major mechanisms implicated in lipopolysaccharide (LPS)-induced AKI. Spina Gleditsiae is a traditional Chinese anti-inflammatory medicine, from which a large number of flavonoids, such as 5-O-methyldihydroquercetin (GS1) and cilicicone B (GS2), were isolated in the present study. Here, we examined the reno-protective effects and potential underlying mechanisms of GS1 and GS2 in mice with LPS-induced AKI. METHODS: We analyzed renal function; the serum metabolic profile, inflammatory cytokine levels, peripheral white blood cell count, renal cell apoptosis, renal oxidant and antioxidant levels, and renal expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), TIR-domain-containing adapter-inducing interferon-ß (TRIF), nuclear factor-ĸB (NF-ĸB), interferon regulatory factor 3 (IRF3), NOD-, LRR- and pyrin domain-containing 3 (NLRP3, inflammasome), cleaved caspase-1, and interleukin 1 receptor type I (IL-1R1) in mice with LPS-induced AKI. RESULTS: GS1 and GS2 improved renal function and significantly reduced the levels of inflammatory cytokines and oxidative stress markers. In addition, PCA score scatter plots suggest that the GS1 and GS2 groups were clustered with the control group, indicating that these compounds contributed to the recovery of mice with AKI toward the normal condition. Moreover, GS1 and GS2 inhibited the expression of TLR4, MyD88, TRIF, p-NF-ĸB, p-IRF3, NLRP3, cleaved caspase-1, and IL-1R1. CONCLUSION: The reno-protective effects of GS1 and GS2 are mediated via the MyD88/TRIF and NLRP3 pathways to reduce inflammation and oxidative stress through TLR4 signaling.

Aerosol inhalation of a hydrogen-rich solution restored septic renal function.

Sepsis-related acute kidney injury (AKI) is known to be caused by inflammation. We explored the renal protective effects of aerosol inhalation of a hydrogen-rich solution (HRS; hydrogen gas dissolved to saturation in saline) in a mouse model of septic AKI. Septic AKI was induced through 18 hours of cecal ligation and puncture. AKI occurred during the early stage of sepsis, as evidenced by increased blood urea nitrogen and serum creatinine levels, pathological changes, renal fibrosis and renal tubular epithelial cell apoptosis, accompanied by macrophage infiltration and M1 macrophage-associated pro-inflammatory cytokine (Il-6 and Tnf-α) generation in renal tissues. Aerosol inhalation of the HRS increased anti-inflammatory cytokine (Il-4 and Il-13) mRNA levels in renal tissues and promoted macrophage polarization to the M2 type, which generated additional anti-inflammatory cytokines (Il-10 and Tgf-ß). Ultimately, aerosol inhalation of HRS protected the kidneys and increased survival among septic mice. HRS was confirmed to promote M2 macrophage polarization in lipopolysaccharide-stimulated RAW 264.7 cells. The TGF-ß1 receptor inhibitor SB-431542 partly reversed the effects of HRS on renal function, fibrosis, tubular epithelial cell apoptosis and senescence in mice. Thus, HRS aerosol inhalation appears highly useful for renal protection and inflammation reduction in septic AKI.

Structural characterization and in vitro-in vivo evaluation of effect of a polysaccharide from Sanguisorba officinalis on acute kidney injury.

We report here an acidic polysaccharide, namely RSP-3, which ameliorates acute kidney injury and is obtained from Sanguisorba officinalis. We extracted and purified two polysaccharides from this herb based on the acidity and screened them for their effect in regulating the immunological activity of macrophages. Among them, RSP-3 exhibited significant anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated macrophages by decreasing TNF-α and IL-6 levels. Subsequently, we found that RSP-3 suppressed ER stress, reduced ROS production and blocked NF-κBp65 translocation. After fully characterizing RSP-3 with a series of analytical technologies, we tested its anti-acute kidney injury (AKI) effect in vivo. In a murine AKI model induced by LPS, treatment with RSP-3 effectively ameliorated renal function. Besides, it decreased the levels of TNF-α and IL-6 in serum and reduced macrophage infiltration in injured kidney tissue. In sum, RSP-3, with a significant protective effect against AKI by showing anti-inflammatory activity, may become a meaningful drug candidate for treatment of AKI.

A dual role of 12/15-lipoxygenase in LPS-induced acute renal inflammation and injury.

Recent studies suggest a potential role of bioactive lipids in acute kidney injury induced by lipopolysaccharide (LPS). The current study was designed to determine the profiling activities of various polyunsaturated fatty acid (PUFA) metabolizing enzymes, including lipoxygenases (LO), cyclooxygenase, and cytochrome P450 in the plasma of LPS-injected mice using LC-MS. Heat map analysis revealed that out of 126 bioactive lipids screened, only the 12/15-LO metabolite, 12-HETE, had a significant (2.24 ±â€¯0.4) fold increase relative to control (P = 0.0001) after Bonferroni Correction (BCF α = 0.003). We then determined the role of the 12/15-LO in LPS-induced acute kidney injury using genetic and pharmacological approaches. Treatment of LPS injected mice with the 12/15-LO inhibitor, baicalein, significantly reduced levels of renal injury and inflammation markers including urinary thiobarbituric acid reactive substance (TBARs), urinary monocyte chemoattractant protein-1 (MCP-1), renal interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Similarly, knocking-out of 12/15-LO reduced levels of renal inflammation and injury markers elicited by LPS injection. Next, we tested whether exogenous supplementation with docosahexaenoic acid (DHA) as a substrate would divert the role of 12/15-LO from being pro-inflammatory to anti-inflammatory via increased production of the anti-inflammatory metabolite. DHA treatment restored the decreased in plasma level of resolvin D2 (RvD2) and reduced renal injury in LPS-injected mice whereas DHA treatment failed to provide any synergistic effects in reducing renal injury in LPS injected 12/15-LO knock-out mice. The ability of RvD2 to protect kidney against LPS-induced renal injury was further confirmed by exogenous RvD2 which significantly reduced the elevation in renal injury in LPS injected mice. These data suggest a double-edged sword role of 12/15-LO in LPS-induced acute renal inflammation and injury, depending on the type of substrate available for its activity.

Pre-Treatment with Curcumin Ameliorates Cisplatin-Induced Kidney Damage by Suppressing Kidney Inflammation and Apoptosis in Rats.

OBJECTIVE: In addition to oxidative stress, inflammation and apoptosis have an important role in the pathogenesis of cisplatin-induced kidney damage. This study aimed to investigate the molecular mechanisms of protective effects of curcumin against cisplatin-induced kidney inflammation and apoptosis in rats. MATERIALS AND METHODS: Eighteen rats were equally divided into three groups; normal (0.5% CMC-Na), cisplatin (CDPP) (7 mg/kg i.p.), and cisplatin+curcumin (CMN100) groups. Curcumin was given at a dose of 100 mg/kg orally for nine days, starts one week before giving a single dose of cisplatin. Kidney and plasma were taken for analysis. RESULTS: Cisplatin challenged rats demonstrated kidney injury as shown by reduced creatinine clearance, increased of plasma BUN, plasma creatinine, and kidney MDA, decreased of kidney GSH levels, and kidney histopathology alterations. Also, cisplatin increased ERK1/2 phosphorylation and NF-κB expression, which subsequently increased mRNA expression of TNF-α, IL-6, KIM-1, NGAL, and Bax/Bcl-2 ratio as well as decreased mRNA expression of IL-10 in kidney tissues. Pre-treatment with curcumin significantly ameliorated inflammation and apoptosis induced by cisplatin. In addition, curcumin downregulated Ctr1 and OCT2 drug transporters as compared to cisplatin group. Histopathological examination furthers confirmed the kidney damage protection effect of curcumin. CONCLUSIONS: These data indicate that curcumin has nephroprotective properties against cisplatin-induced kidney damage in rats and this effect is associated with its anti-inflammatory and anti-apoptosis profiles, in addition to its antioxidant. Hence, curcumin may be useful for preventing kidney damage against cisplatin administration.

Renal regeneration after acute kidney injury.

Acute kidney injury is common and associated with negative renal and patient outcomes. The human kidney has a real but limited regeneration capacity. Understanding renal regeneration may allow us to manipulate this process and thus develop therapeutic weapons to improve patients' outcome. In the first part of this paper we discuss the clinical factors associated with renal recovery: baseline patient particularities, acute kidney injury characteristics and the medical approach taken in the short and long-term. In the second part, the cellular and molecular mechanisms underlying renal regeneration are explored. The immune system seems to have an important role, first promoting inflammation and then tissue healing. Other players, such as cellular senescence, mitochondrial dysfunction, renal haemodynamics and metabolic reprogramming also have a role in renal regeneration. We aim to develop a short review of renal regeneration, offering a holistic view of this process.

RA-XII exerts anti-oxidant and anti-inflammatory activities on lipopolysaccharide-induced acute renal injury by suppressing NF-κB and MAPKs regulated by HO-1/Nrf2 pathway.

Acute kidney injury (AKI) is an abrupt loss of kidney function and severe AKI needs renal replacement therapeutic strategy and has high mortality. RA-XII is a natural cyclopeptide, isolated from the traditional Chinese medicine Rubia yunnanensis, exerting anti-inflammatory and anti-tumor activities. The present study aimed to explore the effects of RA-XII on LPS-induced ACI and the underlying molecular mechanism in TCMK-1 cells in vitro. The results indicated that RA-XII delayed the animal death caused by LPS in mice. The kidney histological changes were markedly attenuated by RA-XII. RA-XII also reduced the serum uric acid, creatinine, BUN and renal 8-OHdG. In addition, RA-XII suppressed LPS-induced oxidative stress in kidney, as evidenced by the up-regulation of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels, and the down-regulation of malondialdehyde (MDA) levels. Additionally, RA-XII enhanced heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions in renal tissue sections. Further, RA-XII reduced the release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6 and IL-18, in renal, which was linked to the inhibition of inhibitor of alpha/nuclear factor kappa B (IκBα/NF-κB) and mitogen-activated protein kinases (MAPKs) pathways. The in vitro study illustrated that the anti-inflammatory effects of RA-XII were partially reversed following Nrf2 and HO-1 inhibition. Together, these findings strongly suggested that RA-XII is a potential agent against acute kidney injury.

The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells.

Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69+CD4+, and CD44+CD4+ T cells was attenuated, but renal Foxp3+CD4+ Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3+CD4+ Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs.

Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats.

BACKGROUND: Gentamicin-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI). The phenotypic alterations that contribute to acute kidney injury include inflammatory response and oxidative stress. Curcumin has a wide range biological functions, especially as an antioxidant. This study was designed to evaluate the renoprotective effects of curcumin treatment in gentamicin-induced AKI. METHODS: Gentamicin-induced AKI was established in female Sprague-Dawley rats. Rats were treated with curcumin (100 mg/kg body mass) by intragastric administration, once daily, followed with an intraperitoneal injection of gentamicin sulfate solution at a dose of 80 mg/kg body mass for 8 consecutive days. At days 3 and 8, the rats were sacrificed, and the kidneys and blood samples were collected for further analysis. RESULTS: The animals treated with gentamicin showed marked deterioration of renal function, together with higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the plasma as compared with the controls. Animals that underwent intermittent treatment with curcumin exhibited significant improvements in renal functional parameters. We also observed that treatment with curcumin significantly attenuated renal tubular damage, apoptosis, and oxidative stress. Curcumin treatment exerted anti-apoptosis and anti-oxidative effects by up-regulating Nrf2/HO-1 and Sirt1 expression. CONCLUSIONS: Our data clearly demonstrate that curcumin protects kidney from gentamicin-induced AKI via the amelioration of oxidative stress and apoptosis of renal tubular cells, thus providing hope for the amelioration of gentamicin-induced nephrotoxicity.

Endothelin-1-mediated inflammation in acute renal failure.

Acute renal failure presents a serious and life-threatening problem in hospitalized patients. Current therapies address the systemic alterations in renal failure. Cellular changes also occur. These changes affect the glomerular filtration rate and the integrity of the glomerular membrane. ET-1, the most potent vasoconstrictor known, has a negative effect on both the rate of filtration and the integrity of the filtering membrane in renal failure. Using ET-1 antagonists along with the current therapies may prove useful in patients.

Plasma levels of the interleukin-6 cytokine family in persons with severe Plasmodium falciparum malaria.

Plasma levels of interleukin (IL)-6, soluble IL-6 receptor, soluble gp130, leukemia inhibitory factor (LIF), and ciliary neutrophic factor (CNTF) were analyzed in 32 patients with severe malaria. Ten had renal failure, 8 had cerebral malaria, and 14 had other causes of severity. Before treatment, the IL-6 and soluble IL-6 receptor plasma levels were significantly higher in persons with cerebral malaria or renal failure than in other groups (P<.01 for both). After initiation of therapy, IL-6 levels dropped within 24 h, but soluble IL-6 receptor levels increased. CNTF levels were significantly reduced in persons with cerebral malaria or renal failure but normalized within 24 h. Plasma concentrations of gp130 and LIF did not differ between the malaria groups or normal controls. Excessive levels of IL-6 could be controlled by a subsequent shedding of the soluble IL-6 receptor, and low-level CNTF expression could contribute to or even result from cerebral malaria or renal failure.