Opioid-induced respiratory depression suspected of drug interaction in a prostate cancer patient: a case report.

BACKGROUND: Many of the drugs used for the treatment and alleviation of symptoms in cancer patients are known to inhibit or induce cytochrome P450 (CYP). Therefore, it is important to pay attention to the drug interactions of opioid analgesics that are metabolized by CYPs, because for example when using oxycodone metabolized by CYP3A4, it is possible that the effect will be attenuated or enhanced by the concomitant use of drugs that induce or inhibit CYP3A4. Aprepitant, an antiemetic drug used in many patients receiving anticancer drugs, is known as a moderate competitive inhibitor of CYP3A4. We experienced a case of respiratory depression caused by opioids, which was suspected to be caused by a drug interaction with antiemetics especially aprepitant. CASE DESCRIPTION: The patient was a 72-year-old man. He had been treated with continuous oxycodone infusion for perianal pain associated with the rectal invasion of prostate cancer. No comorbidities other than renal dysfunction were observed. Oxycodone treatment was started at 48 mg/day, and was increased to 108 mg/day, and then the pain decreased. Once the pain was controlled, chemotherapy was planned. Antiemetics (dexamethasone, palonosetron, and aprepitant) were administered before anticancer drug administration. Approximately 3 hours after antiemetics administration and before the administration of the anticancer drugs, a ward nurse noticed that oversedation and respiratory depression had occurred. When the patient was called, he immediately woke up and was able to talk normally, so the anticancer drugs were administered as scheduled. About 2 hours after the nurse noticed oversedation, the attending physician reduced the dose of oxycodone infusion to 48 mg/day. After that, his drowsiness persisted, but his respiratory condition improved. Despite reducing the dose of oxycodone to less than half, the pain remained stable at numeric rating scale (NRS) 0-1, without the use of a rescue dose. The patient was discharged from the hospital 36 days after the administration of anticancer drugs, without any problems. CONCLUSIONS: The cause of respiratory depression in this case was thought to be a combination of factors, including drug interactions between oxycodone and antiemetics, and oxycodone accumulation due to renal dysfunction.

WIP1 inhibition as a new therapeutic strategy for collapsing glomerulopathy.

Collapsing glomerulopathy (CG) is an aggressive variant of focal and segmental glomerulosclerosis. Understanding the diverse mechanisms that can drive CG promises to uncover new therapeutic strategies. In this issue, Duret et al. identify WIP1 phosphatase as a therapeutic target for CG. Using genetic ablation and pharmacologic inhibition, they show that blockade of WIP1 activity is protective in 2 different mouse models of CG. This study highlights the complex interplay of glomerular signaling pathways in CG and offers hope for targeted therapies.

Effects of adenosine triphosphate, Lacidipine, and Benidipine on 5-fluorouracil-induced kidney damage in rats.

OBJECTIVE: In the present study, the protective effects of adenosine triphosphate (ATP), Benidipine, and Lacidipine on potential kidney damage induced by 5-fluorouracil (5-FU) were investigated in rats. MATERIALS AND METHODS: Totally 48 rats were divided into 8 groups: healthy (HG), 5-FU (FUG), ATP+5-FU (AFU), Benidipine+5-FU (BFU), Lacidipine+5-FU (LFU), ATP+Benidipine+5-FU (ABFU), ATP+Lacidipine+5-FU (ALFU) and Benidipine+Lacidipine+5-FU (BLFU). In a 10-day period, ATP (4 mg/kg) was administered intraperitoneally, and Benidipine (4 mg/kg) and Lacidipine (4 mg/kg) were administered orally once a day. On days 1, 3, and 5, 5-FU (100 mg/kg) was administered intraperitoneally one hour after the drug was administered. Afterward, the rats were euthanized, and kidney tissues were removed. An analysis of malondialdehyde, total glutathione, superoxide dismutase, and catalase was performed on tissues, as well as a histopathological examination. A creatinine and blood urea nitrogen analysis were performed on blood samples. RESULTS: It was revealed that 5-FU decreased the amount of total glutathione, superoxide dismutase, and catalase activities in rat kidney tissues and increased malondialdehyde. Further, increased serum creatinine and blood urea nitrogen levels, as well as histopathological examination of kidney tissues, were found in the 5-FU group. ATP+Benidipine and ATP treatments were the most effective in preventing both biochemical and histopathological changes induced by 5-FU. A treatment with Benidipine improved biochemical and histopathologic data, but not to the same extent as a treatment with ATP+Benidipine and ATP. As a result of Lacidipine+ATP combination, 5-FU-induced biochemical changes in kidney tissue were partially inhibited, but the degree of histopathologic damage remained unchanged. Neither Benidipine+Lacidipine nor Lacidipine showed a protective effect on both biochemical changes and histopathologic damage. CONCLUSIONS: It may be possible to prevent nephrotoxicity by adding ATP + Benidipine or ATP to 5-FU treatment.

ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways. / ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化.

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-ß1 (TGF-ß1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

Estrategias de prevención y tratamiento de la infección por SARS-CoV-2 (Severe Acute Respiratory Coronavirus 2) en pacientes con enfermedad renal crónica: revisión de la literatura / Strategies for prevention and treatment of SARS-CoV-2 infection in patients with chronic kidney disease: Literature review

La COVID-19 ha demostrado ser especialmente agresiva con los pacientes con enfermedad renal crónica (ERC). La menor tasa de respuesta inmunológica y la mayor facilidad para la progresión a formas graves de enfermedad ha propiciado este hecho, que se ha mantenido en la era posvacunal de la pandemia. Paradójicamente, la ERC ha sido excluida de la mayoría de los ensayos clínicos de las principales herramientas terapéuticas desarrolladas frente a SARS-CoV-2. Sin embargo, se ha ido reuniendo experiencia de uso de estos fármacos en distintos estadios de la ERC que avala su uso con garantías de eficacia y seguridad. El objetivo de esta revisión es reunir todas las indicaciones de tratamiento frente a la COVID-19 en los distintos estadios de la enfermedad adaptadas a la ERC en sus distintas fases, incluyendo el tratamiento sustitutivo renal.(AU)

COVID-19 has proven to be particularly aggressive in patients with chronic kidney disease (CKD). The lower immune response rate and the greater susceptibility to progress to severe forms of the disease have contributed to this phenomenon, which has persisted in the post-vaccination era of the pandemic. Paradoxically, CKD has been excluded from most clinical trials of the main therapeutic tools developed against SARS-CoV-2. However, experience in the use of these drugs has been accumulating in different stages of CKD, supporting their use with guarantees of efficacy and safety. The objective of this review is to gather all treatment indications for COVID-19 in the different phases of the disease, tailored to CKD in its various stages, including renal replacement therapy.(AU)

A quantitative review of nanotechnology-based therapeutics for kidney diseases.

Kidney-specific nanocarriers offer a targeted approach to enhance therapeutic efficacy and reduce off-target effects in renal treatments. The nanocarriers can achieve organ or cell specificity via passive targeting and active targeting mechanisms. Passive targeting capitalizes on the unique physiological traits of the kidney, with factors like particle size, charge, shape, and material properties enhancing organ specificity. Active targeting, on the other hand, achieves renal specificity through ligand-receptor interactions, modifying nanocarriers with molecules, peptides, or antibodies for receptor-mediated delivery. Nanotechnology-enabled therapy targets diseased kidney tissue by modulating podocytes and immune cells to reduce inflammation and enhance tissue repair, or by inhibiting myofibroblast differentiation to mitigate renal fibrosis. This review summarizes the current reports of the drug delivery systems that have been tested in vivo, identifies the nanocarriers that may preferentially accumulate in the kidney, and quantitatively compares the efficacy of various cargo-carrier combinations to outline optimal strategies and future research directions. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Astaxanthin treatment reduces kidney damage and facilitates antioxidant recovery in lithium-intoxicated rats.

OBJECTIVE: This study aimed to evaluate the protective effects of astaxanthin against lithium-induced nephrotoxicity, focusing on histopathological changes, oxidative stress modulation, and alteration in the expression of key proteins related to apoptosis and inflammation. METHODS: In this study, 56 male rats were utilized and divided into experimental groups subjected to lithium-induced nephrotoxicity, with and without astaxanthin treatment, over 14 and 28 days. The parameters assessed included oxidative stress markers (MDA, GSH, SOD), protein expression levels of BCL-2, BAX, TNF- α, PI3K, NF-κ B-p65, IL-1ß, and comprehensive histopathological examinations to evaluate the integrity of renal tissue. RESULTS: Lithium exposure led to significant renal damage, as evidenced by histological distortions in renal architecture, increased oxidative stress indicated by elevated MDA levels, and dysregulated expressions of apoptotic and inflammatory proteins. Notably, histopathological analysis revealed glomerular and tubular degeneration in lithium-treated groups. Astaxanthin treatment effectively mitigated these effects, demonstrating its efficacy in reducing lipid peroxidation, rebalancing apoptotic proteins, suppressing pro-inflammatory cytokines, and preserving renal histological structure. The concurrent use of lithium and astaxanthin showed a considerable amelioration of lithium-induced damage, suggesting astaxanthin's role in attenuating the nephrotoxic effects of lithium, both at a molecular and structural level. CONCLUSION: Astaxanthin demonstrates significant renoprotective effects against lithium-induced nephrotoxicity, suggesting its utility as an effective adjunctive therapy. Through its potent antioxidative, anti-inflammatory, and anti-apoptotic actions, astaxanthin effectively reduces renal damage associated with lithium treatment, underscoring its potential for enhancing renal health in patients receiving lithium therapy.

Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax.

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.

Rutin mitigates fluoride-induced nephrotoxicity by inhibiting ROS-mediated lysosomal membrane permeabilization and the GSDME-HMGB1 axis involved in pyroptosis and inflammation.

Fluoride is known to induce nephrotoxicity; however, the underlying mechanisms remain incompletely understood. Therefore, this study aims to explore the roles and mechanisms of lysosomal membrane permeabilization (LMP) and the GSDME/HMGB1 axis in fluoride-induced nephrotoxicity and the protective effects of rutin. Rutin, a naturally occurring flavonoid compound known for its antioxidative and anti-inflammatory properties, is primarily mediated by inhibiting oxidative stress and reducing proinflammatory markers. To that end, we established in vivo and in vitro models. In the in vivo study, rats were exposed to sodium fluoride (NaF) throughout pregnancy and up until 2 months after birth. In parallel, we employed in vitro models using HK-2 cells treated with NaF, n-acetyl-L-cysteine (NAC), or rutin. We assessed lysosomal permeability through immunofluorescence and analyzed relevant protein expression via western blotting. Our findings showed that NaF exposure increased ROS levels, resulting in enhanced LMP and increased cathepsin B (CTSB) and D (CTSD) expression. Furthermore, the exposure to NaF resulted in the upregulation of cleaved PARP1, cleaved caspase-3, GSDME-N, and HMGB1 expressions, indicating cell death and inflammation-induced renal damage. Rutin mitigates fluoride-induced nephrotoxicity by suppressing ROS-mediated LMP and the GSDME/HMGB1 axis, ultimately preventing fluoride-induced renal toxicity occurrence and development. In conclusion, our findings suggest that NaF induces renal damage through ROS-mediated activation of LMP and the GSDME/HMGB1 axis, leading to pyroptosis and inflammation. Rutin, a natural antioxidative and anti-inflammatory dietary supplement, offers a novel approach to prevent and treat fluoride-induced nephrotoxicity.

Mechanisms of norcantharidin against renal tubulointerstitial fibrosis.

Renal tubulointerstitial fibrosis (RTIF) is a common feature and inevitable consequence of all progressive chronic kidney diseases, leading to end-stage renal failure regardless of the initial cause. Although research over the past few decades has greatly improved our understanding of the pathophysiology of RTIF, until now there has been no specific treatment available that can halt the progression of RTIF. Norcantharidin (NCTD) is a demethylated analogue of cantharidin, a natural compound isolated from 1500 species of medicinal insect, the blister beetle (Mylabris phalerata Pallas), traditionally used for medicinal purposes. Many studies have found that NCTD can attenuate RTIF and has the potential to be an anti-RTIF drug. This article reviews the recent progress of NCTD in the treatment of RTIF, with emphasis on the pharmacological mechanism of NCTD against RTIF.

Network pharmacology and experimental validation to reveal the pharmacological mechanisms of Sini decoction against renal fibrosis.

OBJECTIVE: To investigate the mechanism by which Sini decoction (, SND) improves renal fibrosis (Rf) in rats based on transforming growth factor ß1/Smad (TGF-ß1/Smad) signaling pathway. METHODS: Network pharmacology was applied to obtain potentially involved signaling pathways in SND's improving effects on Rf. The targets of SND drug components and the targets of Rf were obtained by searching databases, such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCSMP) and GeenCard. The intersection targets of two searches were obtained and underwent signaling pathway analysis using a Venn diagram. Then experimental pharmacology was utilized to prove and investigate the effects of SND on target proteins in the TGF-ß1/Smad signaling pathway. The Rf rat model was established by unilateral ureteral occlusion (UUO). The expression levels of transforming growth factor, matrix metalloproteinase-9 (MMP-9), matrix metal protease-2 (MMP-2), connective tissue growth factor (CTGF), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined by Masson staining of rat renal tissue, and immunohistochemical methods. The expression levels of Smad3, Smad2, and Smad7 in renal tissue were determined by Western blotting (WB). The mechanism of the improving effects of SND on Rf was investigated based on TGF-ß1/Smad signaling pathway. RESULTS: A total of 12 drug components of Fuzi (Radix Aconiti Lateralis Preparata), 5 drug components of Ganjiang (Rhizoma Zingiber), and 9 drug components of Gancao (Radix Glycy et Rhizoma) were obtained from the database search, and 207 shared targets were found. A total of 1063 Rf targets were found in the database search. According to the Venn diagram, in total, 96 intersection targets were found in two database searches. The metabolic pathways involved included TGF-ß signaling pathway, phosphatidylinositol-3-kinase/serine-threonine protein kinase signaling (PI3K/Akt) pathway, and hypoxia-inducible factor-1 (HIF-1) signaling pathway. Masson staining analysis showed that compared with the model group, the renal interstitial collagen deposition levels in the SSN and SND groups were significantly lower (P < 0.05). Immunohistochemical analysis, compared with the control group, the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the model group were significantly decreased (P < 0.05, P < 0.01), and the positive cell area expression levels of CTGF and TGF-ß1 were significantly increased (P < 0.01). Compared with the model group, the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the SSN and SND groups were significantly increased (P < 0.05, P < 0.01), and the positive cell area expression levels of CTGF and TGF-ß1 in the kidney tissue were significantly decreased (P < 0.05, P < 0.01). WB results showed that the SSN group and the SND group could reduce the expression of Smad2 and Smad3 (P < 0.05) and increase the expression of Smad7 (P < 0.05).

Protecting against ferroptosis in hyperuricemic nephropathy: The potential of ferrostatin-1 and its inhibitory effect on URAT1.

Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro. Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC50 value of 7.37 ± 0.66 µM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.

Demethylzeylasteral protects against renal interstitial fibrosis by attenuating mitochondrial complex I-mediated oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Renal interstitial fibrosis (RIF) is a main pathological process in chronic kidney disease (CKD). Demethylzeylasteral (DML), a major component of Tripterygium wilfordii Hook. f., has anti-renal fibrosis effects. However, its mechanism of action remains incompletely understood. AIM OF THE STUDY: The present study was designed to comprehensively examine the effects of DML on RIF and the underlying mechanisms. MATERIALS AND METHODS: Pathological experiments were performed to determine the therapeutic effect of DML on a mouse model of UUO-induced RIF. To determine the novel mechanisms underlying the therapeutic effects of DML against RIF, a comprehensive transcriptomics analysis was performed on renal tissues, which was further verified by a series of experiments. RESULTS: Pathological and immunohistochemical staining showed that DML inhibited UUO-induced renal damage and reduced the expression of fibrosis-related proteins in mice. Transcriptomic analysis revealed that the partial subunits of mitochondrial complex (MC) I and II may be targets by which DML protects against RIF. Furthermore, DML treatment reduced mitochondrial reactive oxygen species (ROS) levels, consequently promoting ATP production and mitigating oxidative stress-induced injury in mice and cells. Notably, this protective effect was attributed to the inhibition of MC I activity, suggesting a crucial role for this specific complex in mediating the therapeutic effects of DML against RIF. CONCLUSIONS: This study provides compelling evidence that DML may be used to treat RIF by effectively suppressing mitochondrial oxidative stress injury mediated by MC I. These findings offer valuable insights into the pharmacological mechanisms of DML and its potential clinical application for patients with CKD.

Beclin-1-Derived Peptide MP1 Attenuates Renal Fibrosis by Inhibiting the Wnt/ß-Catenin Pathway.

Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix and progressive loss of nephron function, with a lack of effective treatment options in clinical practice. In this study, we discovered that the Beclin-1-derived peptide MP1 significantly inhibits the abnormal expression of fibrosis and epithelial-mesenchymal transition-related markers, including α-smooth muscle actin, fibronectin, collagen I, matrix metallopeptidase 2, Snail1, and vimentin both in vitro and in vivo. H&E staining was employed to evaluate renal function, while serum creatinine (Scr) and blood urea nitrogen (BUN) were used as main indices to assess pathologic changes in the obstructed kidney. The results demonstrated that daily treatment with MP1 during the 14-day experiment significantly alleviated renal dysfunction and changes in Scr and BUN in mice with unilateral ureteral obstruction. Mechanistic research revealed that MP1 was found to have a significant inhibitory effect on the expression of crucial components involved in both the Wnt/ß-catenin and transforming growth factor (TGF)-ß/Smad pathways, including ß-catenin, C-Myc, cyclin D1, TGF-ß1, and p-Smad/Smad. However, MP1 exhibited no significant impact on either the LC3II/LC3I ratio or P62 levels. These findings indicate that MP1 improves renal physiologic function and mitigates the fibrosis progression by inhibiting the Wnt/ß-catenin pathway. Our study suggests that MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis. SIGNIFICANCE STATEMENT: This study indicated that the Beclin-1-derived peptide MP1 effectively mitigated renal fibrosis induced by unilateral ureteral obstruction through inhibiting the Wnt/ß-catenin pathway and transforming growth factor-ß/Smad pathway, thereby improving renal physiological function. Importantly, unlike other Beclin-1-derived peptides, MP1 exhibited no significant impact on autophagy in normal cells. MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis focusing on Beclin-1 derivatives and Wnt/ß-catenin pathway.

Kangxianling formula attenuates renal fibrosis by regulating gut microbiota.

BACKGROUND: Renal fibrosis (RF) produced adverse effect on kidney function. Recently, intestinal dysbiosis is a key regulator that promotes the formation of renal fibrosis. This study will focus on exploring the protective mechanism of Kangxianling Formula (KXL) on renal fibrosis from the perspective of intestinal flora. METHODS: Unilateral Ureteral Obstruction (UUO) was used to construct rats' model with RF, and receive KXL formula intervention for 1 week. The renal function indicators were measured. Hematoxylin-eosin (HE), Masson and Sirus red staining were employed to detect the pathological changes of renal tissue in each group. The expression of α-SMA, Col-III, TGF-ß, FN, ZO-1, and Occuludin was detected by immunofluorescence and immunohistochemistry. Rat feces samples were collected and analyzed for species' diversity using high-throughput sequencing 16S rRNA. RESULTS: Rats in UUO groups displayed poor renal function as well as severe RF. The pro-fibrotic protein expression in renal tissues including α-SMA, Col-III, TGF-ß and FN was increased in UUO rats, while ZO-1 and Occuludin -1 expression was downregulated in colon tissues. The above changes were attenuated by KXL treatment. 16S rRNA sequencing results revealed that compared with the sham group, the increased abundance of pathogenic bacteria including Acinetobacter, Enterobacter and Proteobacteria and the decreased abundance of beneficial bacteria including Actinobacteriota, Bifidobacteriales, Prevotellaceae, and Lactobacillus were found in UUO group. After the administration of KXL, the growth of potential pathogenic bacteria was reduced and the abundance of beneficial bacteria was enhanced. CONCLUSION: KXL displays a therapeutical potential in protecting renal function and inhibiting RF, and its mechanism of action may be associated with regulating intestinal microbiota.

Herb pair of Rhubarb-Astragalus mitigates renal interstitial fibrosis through downregulation of autophagy via p38-MAPK/TGF-ß1 and p38-MAPK/smad2/3 pathways.

BACKGROUND: Chronic kidney disease (CKD) has a high incidence and poor prognosis; however, no effective treatment is currently available. Our previous study found that the improvement effect of the herb pair of Rhubarb-Astragalus on CKD is likely related to the inhibition of the TGF-ß1/p38-MAPK pathway. In the present study, a p38-MAPK inhibitor was used to further investigate the inhibitory effect of Rhubarb-Astragalus on the TGF-ß1/p38-MAPK pathway and its relationship with autophagy. METHODS: A rat model of unilateral ureteral obstruction (UUO) was established, and a subgroup of rats was administered Rhubarb-Astragalus. Renal function and renal interstitial fibrosis (RIF) were assessed 21 d after UUO induction. In vitro, HK-2 cells were treated with TGF-ß1 and a subset of cells were treated with Rhubarb-Astragalus or p38-MAPK inhibitor. Western blotting, immunohistochemistry, and qRT-PCR analyses were used to detect the relevant protein and mRNA levels. Transmission electron microscopy was used to observe autophagosomes. RESULTS: Rhubarb-Astragalus treatment markedly decreased the elevated levels of blood urea nitrogen, serum creatinine, and urinary N-acetyl-ß-D-glucosaminidase; attenuated renal damage and RIF induced by UUO; and reduced the number of autophagosomes and lysosomes in UUO-induced renal tissues. Additionally, Rhubarb-Astragalus reduced the protein and mRNA levels of α-SMA, collagen I, LC3, Atg3, TGF-ß1, p38-MAPK, smad2/3, and TAK1 in renal tissues of UUO rats. Rhubarb-Astragalus also reduced protein and mRNA levels of these indicators in vitro. Importantly, the effect of the p38-MAPK inhibitor was similar to that of Rhubarb-Astragalus. CONCLUSIONS: Rhubarb-Astragalus improves CKD possibly by downregulating autophagy via the p38-MAPK/TGF-ß1 and p38-MAPK/smad2/3 pathways.

Therapeutic potential of BMSC-conditioned medium in an in vitro model of renal fibrosis using the RPTEC/TERT1 cell line.

We investigated the therapeutic potential of bone marrow-derived mesenchymal stem cell-conditioned medium (BMSC-CM) on immortalized renal proximal tubule epithelial cells (RPTEC/ TERT1) in a fibrotic environment. To replicate the increased stiffness characteristic of kidneys in chronic kidney disease, we utilized polyacrylamide gel platforms. A stiff matrix was shown to increase α-smooth muscle actin (α-SMA) levels, indicating fibrogenic activation in RPTEC/TERT1 cells. Interestingly, treatment with BMSC-CM resulted in significant reductions in the levels of fibrotic markers (α-SMA and vimentin) and increases in the levels of the epithelial marker E-cadherin and aquaporin 7, particularly under stiff conditions. Furthermore, BMSC-CM modified microRNA (miRNA) expression and reduced oxidative stress levels in these cells. Our findings suggest that BMSC-CM can modulate cellular morphology, miRNA expression, and oxidative stress in RPTEC/TERT1 cells, highlighting its therapeutic potential in fibrotic kidney disease. [BMB Reports 2024; 57(2): 116-121].

Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Candesartan protects from cisplatin-induced kidney damage via the GDF-15 pathway.

OBJECTIVE: The aim of this study was to explore the protective effect of candesartan against cisplatin-induced kidney damage, with a specific focus on the growth differentiation factor 15 (GDF-15) pathway. MATERIALS AND METHODS: 24 adult female Wistar rats, with a weight range of 200-210 grams, were enrolled in the study. Eight rats were included as a normal control group and did not receive any medication. 16 rats were administered cisplatin at a dosage of 2.5 mg/kg/day twice a week for 4 weeks (total dose 20 mg/kg). Then, they were randomly divided into two groups and treated with 1 ml/kg/day tap water or 8 mg/kg/day candesartan via oral gavage daily for 4 weeks. At the end of the treatment period, animals were sacrificed, and their kidneys were assessed histologically. In addition, plasma malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), creatinine, and GDF-15 levels were assessed. RESULTS: Treatment with candesartan resulted in a significant rise in serum GDF-15 levels and a significant reduction in levels of serum MDA, TNF-α, IL-6, and creatinine compared to the cisplatin and saline group. Candesartan treatment effectively protected the kidney injury, and histopathological examinations of the kidneys confirmed these results. CONCLUSIONS: This study demonstrates that candesartan alleviates cisplatin-induced renal toxicity by further increasing GDF-15, downregulating inflammatory markers, and reducing oxidative stress.