ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25-mediated ubiquitination of ACSL3.

BACKGROUND: Renal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored. METHODS: The mouse model of IRI-AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation-mass spectrometry was performed to identify potential ANKRD1-interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques. RESULTS: First, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno-associated virus (rAAV9)-mitigated ischaemia/reperfusion-induced renal damage and failure. Silencing ANKRD1 enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti-ferroptotic effect of ANKRD1 knockdown. Finally, we showed ANKRD1 facilitated post-translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63-linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury. CONCLUSIONS: Our study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI-AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI. KEY POINTS/HIGHLIGHTS: Ankyrin repeat domain 1 (ANKRD1) is rapidly activated in renal ischaemia‒reperfusion injury (IRI) models in vivo and in vitro. ANKRD1 knockdown mitigates kidney damage and preserves renal function. Ferroptosis contributes to the deteriorating function of ANKRD1 in renal IRI. ANKRD1 promotes acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) degradation via the ubiquitin‒proteasome pathway. The E3 ligase tripartite motif containing 25 (TRIM25) is responsible for ANKRD1-mediated ubiquitination of ACSL3.

LLM-AIx: An open source pipeline for Information Extraction from unstructured medical text based on privacy preserving Large Language Models.

In clinical science and practice, text data, such as clinical letters or procedure reports, is stored in an unstructured way. This type of data is not a quantifiable resource for any kind of quantitative investigations and any manual review or structured information retrieval is time-consuming and costly. The capabilities of Large Language Models (LLMs) mark a paradigm shift in natural language processing and offer new possibilities for structured Information Extraction (IE) from medical free text. This protocol describes a workflow for LLM based information extraction (LLM-AIx), enabling extraction of predefined entities from unstructured text using privacy preserving LLMs. By converting unstructured clinical text into structured data, LLM-AIx addresses a critical barrier in clinical research and practice, where the efficient extraction of information is essential for improving clinical decision-making, enhancing patient outcomes, and facilitating large-scale data analysis. The protocol consists of four main processing steps: 1) Problem definition and data preparation, 2) data preprocessing, 3) LLM-based IE and 4) output evaluation. LLM-AIx allows integration on local hospital hardware without the need of transferring any patient data to external servers. As example tasks, we applied LLM-AIx for the anonymization of fictitious clinical letters from patients with pulmonary embolism. Additionally, we extracted symptoms and laterality of the pulmonary embolism of these fictitious letters. We demonstrate troubleshooting for potential problems within the pipeline with an IE on a real-world dataset, 100 pathology reports from the Cancer Genome Atlas Program (TCGA), for TNM stage extraction. LLM-AIx can be executed without any programming knowledge via an easy-to-use interface and in no more than a few minutes or hours, depending on the LLM model selected.

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

HIF-1 contributes to autophagy activation via BNIP3 to facilitate renal fibrosis in hypoxia in vitro and UUO in vivo.

The molecular basis of renal interstitial fibrosis, a major pathological feature of progressive kidney diseases, remains poorly understood. Autophagy has been implicated in renal fibrosis, but whether it promotes or inhibits fibrosis remains controversial. Moreover, it is unclear how autophagy is activated and sustained in renal fibrosis. The present study was designed to address these questions using the in vivo mouse model of unilateral ureteral obstruction and the in vitro model of hypoxia in renal tubular cells. Both models showed the activation of hypoxia-inducible factor-1 (HIF-1) and autophagy along with fibrotic changes. Inhibition of autophagy with chloroquine reduced renal fibrosis in unilateral ureteral obstruction model, whereas chloroquine and autophagy-related gene 7 knockdown decreased fibrotic changes in cultured renal proximal tubular cells, supporting a profibrotic role of autophagy. Notably, pharmacological and genetic inhibition of HIF-1 led to the suppression of autophagy and renal fibrosis in these models. Mechanistically, knock down of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a downstream target gene of HIF, decreased autophagy and fibrotic changes during hypoxia in BUMPT cells. Together, these results suggest that HIF-1 may activate autophagy via BNIP3 in renal tubular cells to facilitate the development of renal interstitial fibrosis.NEW & NOTEWORTHY Autophagy has been reported to participate in renal fibrosis, but its role and underlying activation mechanism is unclear. In this study, we report the role of HIF-1 in autophagy activation in models of renal fibrosis and further investigate the underlying mechanism.

PIM1 attenuates cisplatin-induced AKI by inhibiting Drp1 activation.

Cisplatin, an effective anti-cancer drug, always causes acute kidney injury (AKI) by inducing mitochondrial damage. PIM1 is a serine/threonine kinase, which has been shown to regulate mitochondrial function. However, the role and mechanisms of PIM1 in cisplatin-induced AKI remain unexplored. This study aimed to investigate the effects of PIM1 in cisplatin-induced AKI and its underlying mechanisms. To established Cisplatin-induced AKI model, mice were given a single intraperitoneal injection(20 mg/kg) and BUMPT cells were treated with cisplatin(20 µM). PIM1 inhibitor AZD1208 was used to inhibit PIM1 and PIM1-experssing adenovirus was used to overexpress PIM1. Drp1 inhibitor P110 and pcDNA3-Drp1K38A were used to inhibit the activation of Drp1 and mitochondrial fission. The indicators of renal function, renal morphology, apoptosis and mitochondrial dysfunction were assessed to evaluate cisplatin-induced nephrotoxicity. We observed that PIM1 was activated in cisplatin-induced AKI in vivo and cisplatin-induced tubular cells injury in vitro. PIM1 inhibition aggravated cisplatin-induced AKI in vivo, while PIM1 overexpression attenuated cisplatin-induced kidney injury in vivo and in vitro. Moreover, inhibiting PIM1 exacerbated mitochondrial damage in mice, but overexpressing PIM1 relieved mitochondrial damage in mice and BUMPT cells. In mice and BUMPT cells, inhibiting PIM1 deregulated the expression of p-Drp1S637, overexpressing PIM1 upregulated the ex-pression of p-Drp1S637. And inhibiting Drp1 activity alleviated cell damage in BUMPT cells with PIM1 knockdown or inhibition. This study demonstrated the protective effect of PIM1 in cisplatin-induced AKI, and regulation of Drp1 activation might be the underlying mechanism. Altogether, PIM1 may be a potential therapeutic target for cisplatin-induced AKI.

Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study.

Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.

PIM1 attenuates renal ischemia-reperfusion injury by inhibiting ASK1-JNK/P38.

Renal ischemia-reperfusion injury (IRI) is the main cause of acute kidney injury (AKI), yet therapeutic approaches to alleviate IRI remain limited. PIM1 (provirus integration site for Moloney murine leukemia virus 1) is a constitutive serine threonine kinase that phosphorylates various substrates to regulate cell death and survival. However, the role of PIM1 in renal IRI remains unclear. This study aims to investigate the effect of PIM1 on renal IRI and explore its downstream regulatory mechanism. In this study, we inhibited or overexpressed PIM1 in mice and cultured proximal tubular cells, and then induced renal IRI model in vivo and hypoxia reoxygenation (HR) model in vitro. Renal function, renal structure injuries and cellular death were assessed to reflect the extent of IRI. The expression of PIM1 and the levels of ASK1, MAPK and their phosphorylated forms were detected by immunoblot. RNA sequencing of kidney cortex was performed to analyze downstream pathway of PIM1 in renal IRI. The results showed that PIM1 expression was significantly upregulated in renal IRI mouse model and in renal tubular cell HR model. AZD1208 (a PIM1 inhibitor) aggravated renal IRI, while PIM1 overexpression ameliorated renal IRI. This was involved in the regulation of the ASK1-MAPK pathway. Moreover, results demonstrated that ASK1 was a downstream target of PIM1 by administering Selonsertib (an inhibitor of ASK1 activity), and inhibiting ASK1 alleviated cell death after HR in PIM1 knockdown cells by reducing JNK/P38 activation. In conclusion, this study elucidated the protective effect of PIM1 on renal IRI, and the underlying mechanism may be related to ASK1-JNK/P38 signaling pathway. Taken together, PIM1 may be a potential therapeutic target for renal IRI.

Primary hyperoxaluria diagnosed after kidney transplantation: a case report and literature review.

BACKGROUND: Primary hyperoxaluria (PH) is a rare inherited autosomal recessive disease caused by disturbed glyoxylate metabolism. The disease is characterized by calcium oxalate crystal deposition in various organs, especially in the kidney. Due to the lack of current understanding of PH, nearly all patients are only initially diagnosed with PH when recurrent lithiasis and progressive end-stage renal disease occur. Many cases are not diagnosed in patients until renal allograft insufficiency occurs after renal transplantation. This case report and literature review aim to emphasize the need for careful pre-transplant PH screening of patients with bilateral nephrocalcinosis or nephrolithiasis. CASE PRESENTATION: Renal allograft insufficiency was diagnosed as PH after kidney transplantation. Here, we detail the complete clinical course, including computed tomography images of the original kidney and renal graft, histopathological images of a biopsy of the transplanted kidney, the results of laboratory and molecular genetic tests, and the treatment. In addition, we reviewed the literature from 2000 to 2021 and analyzed 19 reported cases of PH diagnosed after kidney transplantation, and provide a summary of the characteristics, complications, treatment, and prognosis of these cases. CONCLUSIONS: By reviewing and analyzing these cases, we concluded that patients with a history of nephrocalcinosis or nephrolithiasis in both kidneys need preoperative screening for PH and appropriate treatment before kidney transplantation. Delayed graft function caused by PH is easily misdiagnosed as acute rejection, and needle biopsy should be performed at an early stage.

Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis.

Both endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-ß1-treated HK-2 cells. Interestingly, in both TM- or TGF-ß1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.

Vitamin D/VDR Protects Against Diabetic Kidney Disease by Restoring Podocytes Autophagy.

OBJECTIVE: The present study is to investigate the effect of vitamin D/Vitamin D Receptor (VDR) signaling on podocyte autophagy in diabetic nephropathy. METHODS: Kidney tissue sections from patients with diabetic nephropathy and nontumor kidney were checked under electronic microscope and VDR immunohistochemistry. Diabetic rat models were induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg). Calcitriol treatment was achieved by gavage at dose of 0.1µg/kg/d. Blood, urine and kidney tissue specimens were used for serum, urine biochemistry, histopathology and molecular biology testing. Podocyte cell line MPC-5 was cultured under hyperglycaemic conditions in the absence or presence of 100 nmol/L calcitriol to investigate podocyte injury and autophagy. RESULTS: VDR and autophagosomes in podocytes were significantly decreased in renal biopsy from patients with diabetic nephropathy, compared to healthy kidney tissue. Rats with STZ treatment developed typical diabetic kidney disease with low VDR expression. Calcitriol, the active form of vitamin D, could activate VDR and attenuate diabetic nephropathy including proteinuria and glomerular sclerosis. Calcitriol treatment also alleviated the podocyte foot process fusion, reduced podocyte injury marker desmin and preserved slit diaphragms proteins in diabetic nephropathy. Reduced LC3II/I, Beclin-1 and elevated p62 in renal homogenate and reduced autophagosomes and LC3II in podocytes indicated podocytes autophagy impairment in diabetic nephropathy. Whereas calcitriol treatment restored podocyte autophagy activities. In cultured podocytes, the protective effect of calcitriol against high glucose induced podocyte injury could be abated by autophagy inhibitor chloroquine. CONCLUSION: Our study delivered the evidence that calcitriol/VDR signaling attenuated diabetic nephropathy and podocytes injury by restoring podocytes autophagy. This finding may have potential implication for exploring protective mechanisms of calcitriol/VDR in diabetic nephropathy.

Canagliflozin reduces cisplatin uptake and activates Akt to protect against cisplatin-induced nephrotoxicity.

Cisplatin is a widely used chemotherapy drug with notorious nephrotoxicity. Na+-glucose cotransporter 2 inhibitors are a class of novel antidiabetic agents that may have other effects in the kidneys besides blood glucose control. In the present study, we demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy in C57BL/6 mice and suppresses cisplatin induced renal proximal tubular cell apoptosis in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38 and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by kidney tissues in mice and renal tubular cells in culture. In addition, canagliflozin enhanced the activation of Akt and inhibited the mitochondrial pathway of apoptosis during cisplatin treatment. The protective effect of canagliflozin was diminished by the phosphatidylinositol 3-kinase/Akt inhibitor LY294002. Notably, canagliflozin did not affect the chemotherapeutic efficacy of cisplatin in A549 and HCT116 cancer cell lines. These results suggest a new application of canagliflozin for renoprotection in cisplatin chemotherapy. Canagliflozin may protect kidneys by reducing cisplatin uptake and activating cell survival pathways.

miR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury.

Disruption of mitochondrial dynamics is an important pathogenic event in both acute and chronic kidney diseases, but the underlying mechanism remains poorly understood. Here, we report the regulation of mitofusin-2 (Mfn2; a key mitochondrial fusion protein) by microRNA-214 (miR-214) in renal ischemia-reperfusion that contributes to mitochondrial fragmentation, renal tubular cell death, and ischemic acute kidney injury (AKI). miR-214 was induced, whereas Mfn2 expression was decreased, in mouse ischemic AKI and cultured rat kidney proximal tubular cells (RPTCs) following ATP depletion treatment. Overexpression of miR-214 decreased Mfn2. Conversely, inhibition of miR-214 with anti-miR-214 prevented Mfn2 downregulation in RPTCs following ATP depletion. Anti-miR-214 further ameliorated mitochondrial fragmentation and apoptosis, whereas overexpression of miR-214 increased apoptosis, in ATP-depleted RPTCs. To test regulation in vivo, we established a mouse model with miR-214 specifically deleted from kidney proximal tubular cells (PT-miR-214-/-). Compared with wild-type mice, PT-miR-214-/- mice had less severe tissue damage, fewer apoptotic cells, and better renal function after ischemic AKI. miR-214 induction in ischemic AKI was suppressed in PT-miR-214-/- mice, accompanied by partial preservation of Mfn2 in kidneys. These results unveil the miR-214/Mfn2 axis that contributes to the disruption of mitochondrial dynamics and tubular cell death in ischemic AKI, offering new therapeutic targets.

P53 in kidney injury and repair: Mechanism and therapeutic potentials.

Acute kidney injury (AKI) is a major kidney disease with poor clinical outcome. Besides its acute consequence of high mortality, AKI may also contribute significantly to the occurrence and progression of chronic kidney diseases (CKD). Accumulating evidence has demonstrated that maladaptive and incomplete kidney repair after AKI leads to the development of renal fibrosis and, ultimately, CKD. p53, a well-known tumor suppressor, plays a critical role in AKI and subsequent kidney repair through the regulation of various cell biologic processes, including apoptosis, cell cycle arrest, and autophagy. Despite the notable progress in deciphering the involvement of p53 in kidney injury and repair, the underlying mechanisms of p53 in these pathological processes remain largely unknown. Further investigation in this area is essential for the application of p53 as therapeutic target to prevent and treat AKI or impede its progression to CKD. In this review, we summarize the recent advances in understanding p53 regulation of AKI and kidney repair, pinpoint the potential of p53 as a therapeutic target, and present future research interests and directions.

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF.

BACKGROUND: Immunoglobulin (Ig) A nephropathy (IgAN) is the xFB01;nding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Increasing evidence suggested that retinoic acid (RA) signaling selectively induces IgA isotype switching and basic leucine zipper transcription factor, ATF-like (BATF) controls the global regulators of class switch recombination (CSR) in lymphocytes. Great effort has been paid to identify whether impaired immune regulation along the 'mucosa-bone marrow (BM) axis' play an important role in the pathogenesis of IgAN. METHODS: The aim of the study was to investigate the expression of all-trans-RA (ATRA) and BATF, and to identify their impact on IgA CSR in IgAN patients and rat animal models. Blood samples and tonsillar tissue specimens were obtained from 22 patients with IgAN and 24 patients with chronic tonsillitis as control. RESULTS: Immunohistochemical, RT-PCR and western blotting examination revealed that RA signaling and BATF productions are activated in IgAN patients compared with controls. Lipopolysaccharide and α-hemolytic streptococcus stimulation upregulated RA receptor (RAR) and BATF expression, promote IgA CSR and ATRA productions in tonsil mononuclear cells. RAR alpha (RARα) or BATF siRNA decreases IgA expression. We also built IgAN rat models and found that RARα, BATF and activation-induced cytidine deaminase were upregulated in the peripheral blood, spleen and BM. With ATRA (500 µg/kg body weight) treatment for 8 weeks, IgA deposition on glomeruli and mesangial cells proliferation increased. It also revealed that ATRA activated BATF and IgA CSR in vivo. CONCLUSION: These data point toward the role of RA signaling together with BATF in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with neoantigen results in impaired mucosal and systemic IgA responses.

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages.

BACKGROUND: Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis. METHODS: Male C57BL/6 mice were used for all animal studies (n=9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg·day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 µg/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h. RESULTS: Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1ß and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin. CONCLUSION: Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis.

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.