Targeting oxidative phosphorylation to increase the efficacy of immune-combination therapy in renal cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic renal cell carcinoma (RCC); however, most patients develop de novo or acquired resistance to ICIs. Oxidative phosphorylation (OXPHOS) has been rarely explored as a potential target for correcting ICI resistance. METHODS: We systematically analyzed RNA sequencing and clinical data from CheckMate, JAVELIN Renal 101, and NCT01358721 clinical trials, and clinicopathological data of 25 patients from Tongji Hospital to investigate the relationship between OXPHOS and ICI resistance. The Ndufb8-knockdown Renca cell line was derived to determine the effect of OXPHOS on RCC immunotherapy in vivo. RESULTS: An analysis of the CheckMate series data revealed that high OXPHOS levels are risk factors for ICI in patients with RCC, but are affected by thevon Hippel-Lindau protein (VHL) and hypoxia-inducible factor-1α status. This result is consistent with correlation between clinicopathological characteristics and prognostic observations at our institute. Knockdown of the mitochondrial complex I subunit Ndufb8 of the Renca cell line had no effect on cell growth and migration in vitro, but slowed down cell growth in vivo. Among anti-programmed death ligand 1 (PD-L1)-treated BALB/c mice, shNdufb8 Renca tumors grew slower than shControl Renca tumors and the corresponding mice survived longer. Flow cytometry revealed that CD8+ T cells in shNdufb8 Renca tumors, which were exposed to a lower degree of hypoxia and expressed less programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3), secreted more interferon-γ after stimulation. Immunofluorescence demonstrated that the shNdufb8 Renca tumors had a higher proportion of CD8+ T cells and the proportion of these cells was lower in the hypoxic area. CONCLUSIONS: OXPHOS is a reliable predictor of immunotherapy response in RCC and is more pronounced in metastatic lesions. RCC cells generate a hypoxic tumor microenvironment and inhibit T-cell function through oxidative metabolism, thereby leading to immunotherapy resistance.

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

S1P/S1PR1 axis promotes macrophage M1 polarization through NLRP3 inflammasome activation in Lupus nephritis.

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) as well as the leading cause of mortality in patients. Previous studies revealed that S1P level is elevated in plasma samples of SLE patients and murine lupus models. FTY720, targeting S1P receptors, exhibited therapeutic effects in improving the nephritis symptoms of lupus mouse models. However, few studies have discussed the potential relevance of S1P/S1PR to the pathogenesis of LN. Macrophages have been shown to be an important causative agent of renal inflammation, while the pro-inflammatory M1-type promotes kidney injury and inflammation during LN. Importantly, macrophages express various S1P receptors, and how they respond to S1P in the setting of LN remains unclear. Therefore, we examined the level of S1P in the lupus MRL/lpr mice and explored the ensuing interaction of macrophages and S1P. We found that S1P level was elevated in the MRL/lpr mice with a subsequent enhancement of the S1PR1 expression, and blocking S1PR1 by FTY720, the nephritis symptoms of MRL/lpr mice were improved. Mechanistically, we demonstrated that elevated S1P level increase the M1-type macrophage accumulation. And the in-vitro studies proved that S1P/S1PR1 was involved in the promotion of macrophage polarization towards M1 type through activation of NLRP3 inflammasome. These findings confer a novel role to macrophage S1PR1 and provide a new perspective for targeting S1P during LN.

SIRT1 slows the progression of lupus nephritis by regulating the NLRP3 inflammasome through ROS/TRPM2/Ca2+ channel.

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory disease associated with autoantibody formation. Lupus nephritis (LN) is one of the most severe organ manifestations of SLE. The inflammatory response is a key factor in kidney injury, and the NLRP3 inflammasome is frequently associated with the pathogenesis of LN. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD +)-dependent histone deacetylase, is a promising therapeutic target for preventing renal injury. However, the mechanism of SIRT1 in LN remains unclear. Here, we aimed to investigate the mechanism by which SIRT inhibits the NLRP3 inflammasome to slow the progression of LN. We detected the expression of SIRT1 and the infiltration of macrophages in MRL/lpr mice; the results showed that the expression of SIRT1 was decreased, and the symptoms of lupus nephritis were relieved after the use of resveratrol, which upregulated SIRT1. In vitro studies showed that after lipopolysaccharide (LPS) stimulation, SIRT1 expression decreased, and the NLRP3 inflammasome was activated. Upregulation of SIRT1 inhibits NLRP3 inflammasome activation and assembly by interfering with two signalling pathways. First, SIRT1 affects NF-κB expression, transcription, and inflammatory cytokine expression. Second, SIRT1 modulates calcium influx induced by transient receptor potential channel M2 (TRPM2), which could be partly due to the inhibition of reactive oxygen species (ROS) production. Our findings suggest that upregulated SIRT1 inhibits the NLRP3 inflammasome to slow the progression of lupus nephritis by regulating NF-κB and ROS/TRPM2/Ca2+ channels. This study reveals a new anti-inflammatory mechanism of SIRT1, suggesting that SIRT1 may be a potential therapeutic target for the prevention of LN.

Nanoscale metal-organic framework delivers rapamycin to induce tissue immunogenic cell death and potentiates cancer immunotherapy.

Rapamycin has great potential in the antitumor application, but its therapeutic effect is seriously affected by poor water solubility, targeting ability, and low bioavailability. Here, we constructed a novel composite nanomaterial with PCN-224 as a drug carrier and loaded rapamycin, named R@BP@HA. The nanoplate not only improves targeting, but also synergizes rapamycin with PCN-224 to effectively promote tumor cell apoptosis, which subsequently causes immunogenic cell death (ICD), and shows strong therapeutic effect in 4T1 breast cancer model. The treatment effect depends on three main points:(i)Proapoptotic effect of rapamycin on tumor cells;(ii)ROS production by PCN-224-mediated photodynamic therapy;(iii)ICD induced DC maturation, increased immune response and promoted T cell proliferation and differentiation. This nanoplate offers potential antitumor efficacy in combination with chemotherapy, photodynamic therapy, and immunotherapy.

Cytoreductive partial and radical nephrectomies provide equivalent oncologic outcomes in T1-2M1 renal cell carcinoma.

Background: To compare the effectiveness of cytoreductive partial nephrectomy (CPN) and cytoreductive radical nephrectomy (CRN) in the treatment of metastatic T1-T2 renal cell carcinoma (RCC). Methods: We obtained the clinical and pathological data of patients with metastatic T1-T2 RCC who underwent CPN or CRN from the Surveillance, Epidemiology, and End Results (SEER) database (https://seer.cancer.gov). Propensity score matching (PSM) was used to balance differences in characteristics between CPN and CRN cases. Kaplan-Meier survival analysis and univariate and multivariate Cox regression were used to assess the effect of partial nephrectomy (PN) versus radical nephrectomy (RN) on overall survival (OS) and cancer-specific survival (CSS). Results: After screening, 866 eligible cases were obtained. During the 1-107 months of follow-up, 500 patients died, 453 (90.6%) of whom died of RCC. The tumor size in the CRN group was significantly greater than that in the CPN group. Kaplan-Meier survival analysis showed that there was no significant difference in OS and CSS between the CPN group and the CRN group before and after matching. Univariate and multivariate Cox regression analysis found that the risk factors for OS were older age at diagnosis [hazard ratio (HR) =1.02, P=0.008], non-clear cell renal cell carcinoma (ccRCC) pathological type (HR =1.69, P=0.002), number of metastases ≥2 (HR =2.13, P<0.001), and regional lymph node involvement (HR =2.22, P=0.004), while the risk factors for CSS were non-ccRCC pathological type (HR =1.51, P=0.021) and the number of metastases ≥2 (HR =2.24, P <0.001). Conclusions: CPN can provide similar oncologic outcomes as can CRN in T1-2M1 cases, and tumor metastatic burden is a major risk factor for survival in these patients with metastatic renal cell carcinoma (mRCC).

Non-SMC condensin I complex subunit H participates in anti-programmed cell death-1 resistance of clear cell renal cell carcinomas.

Non-SMC condensin I complex subunit H (NCAPH) is reported to play an important role and be a poor prognostic factor in various cancers. However, the function and regulatory mechanism of NCAPH in clear cell renal cell carcinoma (ccRCC) remain unknown. The roles of NCAPH on ccRCC growth were detected in vitro and in vivo assays. The regulatory mechanism of NCAPH was explored by immunoprecipitation assay, ubiquitination assay, ChIP assay, RIP assay, luciferase reporter assay and RNA pull-down assay. The role of NCAPH in immunoregulation also was explored by flow cytometry, T cell-mediated tumour cell killing assay and immune-competent mouse model. In this research, we displayed that NCAPH was upregulated in ccRCC and patients with elevated NCAPH expression had an undesirable prognosis. Functionally, NCAPH depletion restrained ccRCC growth in vitro and in vivo. The elevated NCAPH was attributed to FOXP3-mediated transcription, FUS-mediated transcription splicing and METTL3-mediated m6A modification. Moreover, YTHDC1 promoted NCAPH mRNA nuclear export, and IGF2BP3 enhanced NCAPH mRNA stability in an m6A-dependent manner. NCAPH increased PD-L1 expression by inhibiting the degradation of ß-catenin in ccRCC cells, which further facilitated aerobic glycolysis and immune tolerance of ccRCC. Collectively, our findings display the vital function of NCAPH in ccRCC and uncover that NCAPH may be regarded as a potential therapeutic target to reverse the immune tolerance of ccRCC.

Prognostic indicators for survival in renal cell carcinoma with venous thrombus and development of predictive nomograms.

Background: Previous predictive models of prognosis of patients with renal cell carcinoma (RCC) and venous tumour thrombus (VTT) didn't included patients have not undergoing radical nephrectomy (RN). We analysed both patients receive RN or not to investigate the prognostic factors of survival for patients with RCC and VTT comprehensively. Methods: The clinical data of patients with RCC and VTT diagnosed from 2000-2018 in the Surveillance Epidemiology and End Results (SEER) database were downloaded and compared with the clinical data of patients with VTT admitted to the Department of Urology of the Tongji Hospital (TJH) from 2004-2020. The matched cases were divided into a training set and a validation set. The training set was used to establish nomograms based on key prognostic factors. The reliability of the nomograms for predicting the survival of patients in the training set, those in the validation set and TJH patients and was evaluated by C-indexes, ROC curves and calibration curves. Results: Multivariate Cox regression analysis identified nine prognostic factors for overall survival (OS): age, tumour size, histologic classification, nuclear grade, location of VTT, N stage, M stage, surgery, and systemic treatments (P<0.001). Nomograms for OS and cancer specific survival (CSS) were established based on key prognostic factors obtained from the multivariate analysis. The C-indexes of the nomogram for predicting OS in the training set, validation set, TJH cohort were 0.762 (95% CI: 0.746-0.778), 0.718 (95% CI: 0.687-0.749), and 0.819 (95% CI: 0.745-0.893), respectively. The calibration curves are all close to a straight line with a slope of 1. Based on the ROC curves, the nomograms had greater areas under the curve (AUCs) than the tumor, node and metastasis (TNM) staging system in predicting the 3-year OS and CSS. All three validations showed that the nomograms established based on key prognostic factors have reliable accuracy in predicting the survival of both TJH and SEER patients who developed RCCs with VTT. Conclusions: Beside the location of VTT, the tumour size can also predict the survival of patients with RCC and VTT. Nomograms based on key prognostic factors can predict the survival of patients from both America and central China with reliable accuracy.

Blockage of TIM-3 relieves lupus nephritis by expanding Treg cells and promoting their suppressive capacity in MRL/lpr mice.

T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3) is an important immune checkpoint protein that is expressed in Tregs and affects their function. However, the expression and role of TIM-3 in modulating regulatory T cells (Tregs) in lupus nephritis (LN) are still unknown. In this study, we found that the percentage of TIM-3+ cells among spleen lymphocytes, CD4+ T cells and Tregs was higher in MRL/lpr mice than in MpJ mice. TIM-3high CD4+ T cells and TIM-3high Tregs were mainly responsible for the increase. The percentage of Tregs in TIM-3high CD4+ T cells was lower than that in TIM-3low CD4+ T cells, and the expression of CTLA-4 and IL-10 was lower in TIM-3high Tregs than in the TIM-3low Tregs in MRL/lpr mice. Blockade of TIM-3 in vivo significantly increased the Treg population and the expression of CTLA-4 and IL-10 in Tregs, thus relieving the LN symptoms and pathology in MRL/lpr mice. Additionally, bioinformatics analysis indicated that TIM-3 regulates Treg cells in LN mainly through cytokine-cytokine receptor interactions, the PI3K-Akt signaling pathway, the T cell receptor signaling pathway, Th17 cell differentiation and the FoxO signaling pathway. Together, our study has demonstrated that TIM-3 regulates Tregs in LN and that overexpression of TIM-3 in CD4+ T cells and Tregs leads to Treg quantity and quality deficiency in MRL/lpr mice. Blockade of TIM-3 protects against LN by expanding Tregs and enhancing their suppressive capacity. Finally, TIM-3 might be a potential therapeutic target for the treatment of LN.

Effectiveness of GnRH Antagonists and Agonists in Patients with Hormone-Sensitive Prostate Cancer: A Retrospective Study.

Objective: To assess the effectiveness of gonadotropin-releasing hormone (GnRH) antagonists and agonists in the treatment of patients with hormone-sensitive prostate cancer (HSPC), thus providing valid data support for their clinical treatment. Methods: We collected 52 and 65 HSPC patients treated with GnRH antagonists and agonists, respectively, in Tongji Hospital, Tongji Medical College of HUST between May 2019 and April 2021. Prostate-specific antigen (PSA) levels before and after treatment were recorded and analyzed. Further, univariate and multivariate logistic regressions were used to analyze the influencing factors of PSA control rate in HSPC patients. Results: In patients receiving antagonist, the control rate of prostate-specific antigen (PSA) was 54.28% and 88% without and with abiraterone, respectively, and 47.91% and 72% in patients treated using agonist without and with abiraterone. In 32 pairs of patients obtained via propensity score matching, the PSA control rates were 84.38% and 53.13% for those receiving antagonists and agonists, respectively, and 66.67% and 50% for those without abiraterone, respectively. In addition, univariate logistic regression analysis showed that the type of androgen deprivation therapy (ADT) drugs and combined use of abiraterone had a significant effect on the control rate of PSA. Further multivariate logistic regression revealed that GnRH antagonists in ADT drugs were risk factors for PSA control rate. Conclusion: The PSA control rate of HSPC patients treated with GnRH antagonist is significantly higher than that of the agonist group, and the use of GnRH antagonist is an independent predictor of PSA control rate.

Epigenetic activation of RBM15 promotes clear cell renal cell carcinoma growth, metastasis and macrophage infiltration by regulating the m6A modification of CXCL11.

Clear cell renal cell carcinoma (ccRCC) is a common kidney malignancy that is characterized by poor prognosis. RNA-binding motif protein 15 (RBM15) has been identified as an oncogene in multiple tumors. Nevertheless, the function and mechanism of RBM15 in ccRCC are not clear. In this study, RBM15 was found to be upregulated in ccRCC cells and tissues. RBM15 enhanced the proliferation, clone formation, migration, invasion and epithelial-interstitial transition of ccRCC cells. Enhanced RBM15 was caused by the abundant histone 3 acetylation modification of the RBM15 promoter induced by EP300/CBP. RBM15 enhanced the stability of CXCL11 mRNA in an m6A-dependent manner. Moreover, RBM15 was found to promote macrophage infiltration and M2 polarization by promoting the secretion of CXCL11 in ccRCC cells in vitro and in vivo. Our findings highlight the function of RBM15 in ccRCC and reveal a novel identified EP300/CBP-RBM15-CXCL11 signaling axis, which promotes ccRCC progression and provides new insight into ccRCC therapy.

Heterotopic Ossification of the Inferior Vena Cava Wall: A Case Report and Literature Review.

Masses of the inferior vena cava (IVC) are very diverse, most of which are thrombus and tumor thrombus, whereas heterotopic ossification of IVC has never been reported. Heterotopic ossification (HO) is the formation of mature lamellar bone outside normal bones and in soft tissues. Some researchers believe that HO is a manifestation of vascular calcification. Here we present a case of HO of the inferior vena cava (IVC) wall. A 68 year old female patient complaining hypertension and palpitation and diagnosed with a retroperitoneal mass was found to have a primary mass of the inferior vena cava wall during surgery. Histopathological examination after surgical resection revealed that the mass was mainly composed of mature bone tissues and hematopoietic tissues of bone marrow, there was no recurrence and the patient was symptom-free 15 months after the surgery. HO of the inferior vena cava wall is very rare, with large volume it can affect the circulation, and this case remind us that it can be cured by surgical resection.

Probiotics alleviate autoimmune hepatitis in mice through modulation of gut microbiota and intestinal permeability.

Autoimmune hepatitis (AIH) is an immune-mediated type of chronic liver inflammation accompanied by intestinal flora imbalance. Probiotics have been reported to ameliorate imbalances in the intestinal flora. This study aimed to investigate the effects of compound probiotic in the AIH mouse model. AIH mice were gavaged with compound probiotic and injected intraperitoneally with dexamethasone (dex) for 42 days. The results showed that these treatments suppressed hepatic inflammatory cell infiltration, serum transaminase, and Th1 and Th17 cells. However, Treg cells were increased only in the probiotics group, which indicates an immunomodulatory role of the compound probiotic. The compound probiotic maintained intestinal barrier integrity, blocked lipopolysaccharide (LPS) translocation, and inhibited the activation of the TLR4/NF-κB pathway and the production of inflammatory factors in the liver and ileum. Moreover, the compound probiotic treatment increased the abundance of beneficial bacteria and reduced the abundance of potentially harmful bacteria in gut. Compound probiotic may improve ileal barrier function while increasing the diversity of the intestinal flora, blocking the translocation of gut-derived LPS to the liver and therefore preventing activation of the TLR4/NF-κB pathway. The resulting inhibition of pro-inflammatory factor production facilitates AIH remission.

Role of sphingosine-1-phosphate mediated signalling in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a highly prevalent autoimmune disease characterized by the malfunction of the immune system and the persistent presence of an inflammatory environment. Multiple organs can be affected during SLE, leading to heterogeneous manifestations, which eventually result in the death of patients. Due to the lack of understanding regarding the pathogenesis of SLE, the currently available treatments remain suboptimal. Sphingosine-1-phosphate (S1P) is a central bioactive lipid of sphingolipid metabolism, which serves a pivotal role in regulating numerous physiological and pathological processes. As a well-recognized regulator of lymphocyte trafficking, S1P has been shown to be closely associated with autoimmune diseases, including SLE. Importantly, S1P levels have been found to be elevated in patients with SLE. In murine models of lupus, the increased levels of S1P also contribute to disease activity and organ impairment. Moreover, data from several studies also support the hypothesis that S1P receptors and its producer-sphingosine kinases (SPHK) may serve as the potential targets for the treatment of SLE and its co-morbidities. Given the significant success that intervening with S1P signaling has achieved in treating multiple sclerosis, further exploration of its role in SLE is necessary. Therefore, the aim of the present review is to summarize the recent advances in understanding the potential mechanism by which S1P influences SLE, with a primary focus on its role in immune regulation and inflammatory responses.

Study on Protection of Human Umbilical Vein Endothelial Cells from Amiodarone-Induced Damage by Intermedin through Activation of Wnt/ß-Catenin Signaling Pathway.

Amiodarone (AM) is one of the most effective antiarrhythmic drugs and normally administrated by intravenous infusion which is liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. Intermedin (IMD), a member of calcitonin family, has a broad spectrum of biological effects including anti-inflammatory effects, antioxidant activities, and antiapoptosis. But now, the protective effects of IMD against amiodarone-induced phlebitis and the underlying molecular mechanism are not well understood. In this study, the aim was to investigate the protective efficiency and potential mechanisms of IMD in amiodarone-induced phlebitis. The results of this study revealed that treatment with IMD obviously attenuated apoptosis and exfoliation of vascular endothelial cells and infiltration of inflammatory cells in the rabbit model of phlebitis induced by intravenous infusion of amiodarone compared with control. Further tests in vitro demonstrated that IMD lessened amiodarone-induced endothelial cell apoptosis, improved amiodarone-induced oxidative stress injury, reduced inflammatory reaction, and activated the Wnt/ß-catenin signal pathway which was inhibited by amiodarone. And these effects could be reversed by Wnt/ß-catenin inhibitor IWR-1-endo, and si-RNA knocked down the gene of Wnt pathway. These results suggested that IMD exerted the protective effects against amiodarone-induced endothelial injury via activating the Wnt/ß-catenin pathway. Thus, IMD could be used as a potential agent for the treatment of phlebitis.

The p70S6K/PI3K/MAPK feedback loop releases the inhibition effect of high-dose rapamycin on rat mesangial cell proliferation.

Glomerular mesangial cell (MC) proliferation is one of the causative factors of glomerular diseases and one of their prominent pathological features. Rapamycin can inhibit MC proliferation and slow the progression to chronic renal fibrosis. The present study was designed to observe the role of rapamycin in MC proliferation and to explore the mechanism by which rapamycin acts on Akt and MAPK/ERK1/2 pathways in mesangial cells. MTT assay and flow cytometry were used to evaluate the proliferation and the cell cycle phase of glomerular mesangial cells respectively. The mRNA expression level of p70S6K was detected by RT-qPCR. Western blotting was performed to determine p70S6K, PI3K/Akt, and PI3K/MAPK protein expression. We found that rapamycin could reduce mesangial cell proliferation and arrest the cell cycle in the G1 phase, however the inhibition effect of 1000 nmol/L rapamycin was not higher than that in the 100 nmol/L group. The results of western blotting showed that 1000 nmol/L rapamycin more significantly inhibited the phosphorylation of p70S6K than 100 nmol/L, suggesting there should be another signaling pathway that activates the proliferation of MCs. Moreover, our results revealed that 1000 nmol/L rapamycin led to Raf1-MEK1/2-ERK pathway activation through a p70S6K-PI3K-mediated feedback loop in MCs. This study demonstrated that high-dose rapamycin leads to ERK1/2 activation through a p70S6K/PI3K/MAPK feedback loop in rat MCs, thus reducing the inhibitory effect of rapamycin on MC proliferation.

Experimental study on renoprotective effect of intermedin on diabetic nephropathy.

Intermedin(IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CT/CGRP) family that has anti-inflammatory, antioxidant and anti-apoptosis properties. This study aimed to evaluate the renoprotective effects of IMD on podocyte apoptotic loss and slit diaphragm protein deficiency the kidneys of rats with in streptozotocin (STZ) induced diabetes in high glucose-exposed podocytes. Our results showed that IMD significantly attenuated proteinuria, and alleviated the abnormal alterations in glomerular ultrastructure in vivo. IMD also improved the induction of slit diaphragm proteins, and restored the decreased Bcl-2 expression and suppressed Bax and caspase-3 induction in the diabetic glomeruli. In addition, IMD attenuated podocyte apoptosis and filamentous actin (F-actin) rearrangement in high glucose-exposed podocytes. Exposure to high glucose elevated the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress in renal podocytes, and IMD treatment blocked such ER stress responses pertinent to podocyte apoptosis and reduced synthesis of slit diaphragm proteins in vivo and in vitro. These observations demonstrate that targeting ER stress is an underlying mechanism of IMD-mediated amelioration of diabetes-associated podocyte injury and dysfunction.

Partial and Radical Nephrectomy Provides Equivalent Oncologic Outcomes in pT3a Renal Cell Carcinoma: A Population-Based Study.

PURPOSE: To compare the cause-specific survival (CSS) and overall survival (OS) of patients with localized T3a renal cell carcinoma (RCC) after partial nephrectomy (PN) or radical nephrectomy (RN). METHODS: We obtained the demographic and clinicopathological data of 7,127 patients with localized T3a RCC and who underwent PN or RN from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were divided into fat invasion cohort and venous invasion cohort for subsequent analysis. Kaplan-Meier analysis (KMA) and univariate and multivariate Cox proportional hazards regression analyses were used to evaluate the effects of PN or RN on OS and CSS. Meanwhile, 65 cases with clinical T1 (cT1) RCC upstaged to pathological T3a (pT3a) who were treated in Tongji Hospital (TJH) from 2011 to 2020 and underwent PN or RN were identified. RESULTS: In the study cohort, 2,085 (29.3%) patients died during the 1-172 months' follow-up, of whom 1,155 (16.2%) died of RCC. In the two cohorts of fat invasion and venous invasion, KMA indicated that the PN group had favorable survival (p < 0.001). However, after propensity score matching (PSM), univariate and multivariate Cox regression analyses showed that the PN and RN groups had comparable CSS in the fat invasion cohort (p = 0.075) and the venous invasion cohort (p = 0.190). During 1-104 months of follow-up, 9 cases in the Tongji cohort had disease recurrence. There was no significant difference in recurrence-free survival between the RN group and the PN group (p = 0.170). CONCLUSIONS: Our analysis showed that after balancing these factors, patients with localized pT3a RCC receiving PN or RN can achieve comparable oncologic outcomes. PN is safe for selected T3a patients.

Intermedin Alleviates Renal Ischemia-Reperfusion Injury and Enhances Neovascularization in Wistar Rats.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and increases the risk of subsequently developing chronic kidney disease. Angiogenesis has been shown to play an important role in reducing renal injury after ischemia reperfusion. In this study, we investigated whether IMD could reduce renal IRI by promoting angiogenesis. METHODS: The kidneys of Wistar rats were subjected to 45 min of warm ischemia followed by 24 h of reperfusion. IMD was overexpressed in vivo using the vector pcDNA3.1-IMD transfected by an ultrasound-mediated system. The renal injury after ischemia reperfusion was assessed by detection of the serum creatinine concentration and histologic examinations of renal tissues stained by PAS and H&E. Real-time PCR and Western blotting were used to determine the mRNA and protein levels, respectively. Histological examinations were used to assess the expression of CD31, MMP2, MMP9, ET-1, VEGF and VEGFR2 in tissues. RESULTS: Renal function and renal histological damage were significantly ameliorated in IMD-transfected rats after ischemia reperfusion. Compared to the IRI, IMD significantly promoted angiogenesis. IMD also upregulated the protein and mRNA expression levels of VEGF and VEGFR2 and downregulated the expression level of MMP2, MMP9 and ET-1. CONCLUSION: IMD could protect the kidney after renal ischemia-reperfusion injury by promoting angiogenesis and reducing the destruction of the perivascular matrix.

Evaluation of the inhibitory effect of tacrolimus combined with mycophenolate mofetil on mesangial cell proliferation based on the cell cycle.

The inhibition of mesangial cell proliferation has become an important therapy for the prevention of glomerular proliferation­associated diseases. The combined application of immunosuppressants with multiple targets presents a novel direction in the treatment of kidney diseases. The present study was designed to explore the inhibitory effects of tacrolimus (TAC) combined with mycophenolate mofetil (MMF) on the proliferation of mesangial cells based on the cell cycle. In vitro, the levels of the proliferation index markers, Ki67 and cyclin D1, in human mesangial cells (HMCs) were determined by immunofluorescence staining and western blot analysis, respectively. In mice with lupus nephritis (LN), the proliferation of mesangial cells was determined using PAS and Masson's trichrome staining, while immunohistochemistry was used to detect Ki67 and western blot analysis was employed for the evaluation of cyclin D1 levels. The expression of platelet­derived growth factor (PDGF), a proliferation­associated protein, was estimated using immunohistochemistry and western blot analysis. In patients with LN, Ki67, cyclin D1 and PDGF expression was estimated by immunohistochemistry. The transforming growth factor­ß1/Smad pathway influenced by TAC and the p38 pathway influenced by MMF were also examined by western blot analysis. The results suggested that the combination of TAC and MMF at half the concentration based on the cell cycle was more effective than monotherapy in inhibiting mesangial cell proliferation in vitro and in vivo. TAC inhibited HMC proliferation by affecting the Smad2 signaling pathway. MMF inhibited HMC proliferation by affecting the p38 signaling pathway. Combined treatment with TAC and MMF significantly improved the clinical indexes of patients with LN without severe adverse effects. On the whole, the findings of the present study validate and reinforce the potential use of the combination of TAC and MMF for the treatment of mesangial proliferative diseases.