Diabetic kidney disease (DKD) is a common complication, affecting approximately 40% of patients with diabetes and imposing substantial health and economic burdens worldwide. As DKD prevalence rises, existing treatments remain limited in efficacy, necessitating innovative therapeutic strategies. Soluble guanylate cyclase (sGC) modulators, including activators and stimulators, have emerged as promising treatments by enhancing cyclic guanosine monophosphate production, thereby exerting vasodilatory, anti-inflammatory, and anti-fibrotic effects. Preclinical studies have demonstrated their efficacy in improving renal function and reducing proteinuria in DKD models. Notably, clinical trials involving sGC activators, such as avenicguat, suggest potential benefits in managing DKD, particularly in combination with renin-angiotensin-aldosterone system inhibitors. While initial findings indicate renal protection and good tolerability, further large-scale studies are needed to confirm long-term efficacy and safety. The development of sGC modulators offers hope for improving DKD outcomes and reducing its global healthcare burden.

Telitacicept, a B lymphocyte stimulator/A proliferation-inducing ligand dual-target fusion protein, mainly used for IgA nephropathy and systemic lupus erythematosus. We present two cases where adult patients with IgA vasculitis (IgAV) nephritis were successfully treated with Telitacicept, experienced no adverse reactions during the follow-up. Therefore, Telitacicept represents a promising additional treatment option for patients suffering from IgA vasculitis (IgAV).

RATIONALE:Membranous nephropathy (MN) is an important and common cause of nephrotic syndrome in adults. Overlap syndrome is an infrequent clinical subgroup characterized by the coexistence of autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis. Coexistence of MN and autoimmune liver diseases is rare. Several reports have documented the concurrent presence of multiple autoimmune diseases, suggesting a potential mechanism linking these disorders. PATIENTS CONCERNS:A 53-year-old male patient diagnosed with phospholipase A2 receptor-related MN accompanied by recurrent increases in aminotransferases during treatment. DIAGNOSES:The patient was finally diagnosed as MN with primary biliary cholangitis-autoimmune hepatitis overlap syndrome based on histopathological findings. INTERVENTIONS:A combination of rituximab, oral methylprednisolone, and ursodeoxycholic acid. OUTCOMES:The patient achieved complete immunological remission and partial remission of proteinuria. LESSONS:We encountered a unique case with autoimmune disease of both liver and kidney. Treatment plans should be tailored to each patient's specific condition since there is no standard protocol. The pathological mechanisms of overlapping autoimmune diseases require further understanding.

Diabetic nephropathy, as a severe microvascular complication of diabetes, manifests in four clinical types: classic, albuminuria regression, a rapid decline in kidney function (RDKF), and non-proteinuric or non-albuminuric DKD. Rapidly progressive diabetic nephropathy advances to end-stage renal disease more swiftly than the typical form, posing significant risks. However, a comprehensive understanding of rapidly progressive diabetic nephropathy is currently lacking. This article reviewed latest developments in genetic and clinical risk factors associated with rapidly progressive diabetic nephropathy, aiming to broad perspectives concerning the diagnosis and interventions of this condition.

The pathogenesis of diabetic kidney disease (DKD) is complicated. Current clinical treatments fail to achieve satisfactory efficacy in the prevention of DKD progression, it urgently needs novel and effective treatment for DKD. In this study, we firstly demonstrated that renal lipid metabolism abnormality and inflammation significantly changed in DKD conditions by mining public transcriptomic data of DKD patient samples. KEGG analysis further exhibited the critical role of vascular endothelial growth factor B (VEGF-B) and interleukin 17A (IL-17A) signal pathways in DKD progression, indicating that VEGF-B and IL-17A might be the promising targets for DKD treatment. Then the potential of a novel combination therapy, anti-VEGF-B plus anti-IL-17A antibody, was evaluated for DKD treatment. Our results demonstrated that simultaneous blockade of VEGF-B and IL-17A signaling with their neutralizing antibodies alleviated renal damage and ameliorated renal function. The therapeutic effectiveness was not only related to the reduced lipid deposition especially the neutral lipids in kidney but also associated with the decreased inflammation response. Moreover, the therapy alleviated renal fibrosis by reducing collagen deposition and the expression of fibronectin and α-SMA in kidney tissues. RNA-seq analysis indicated that differential expression genes (DEGs) in db/db mice were significantly clustered into lipid metabolism, inflammation, fibrosis and DKD pathology-related pathways, and 181 of those DEGs were significantly reversed by the combinatory treatment, suggesting the underlying mechanism of administration of anti-VEGF-B and anti-IL-17A antibodies in DKD treatment. Taken together, this study identified that renal lipid metabolism abnormality and inflammation were critically involved in the progression of DKD, and simultaneous blockade of VEGF-B and IL-17A signaling represents a potential DKD therapeutic strategy.

Diabetic nephropathy (DN), the principal pathogeny of end-stage renal disease (ESRD), is related to metabolic disorders, chronic inflammation, and oxidative stress. It was reported that high expression of interleukin-17A (IL-17A) was intimately related to the progression of DN, and targeting IL-17A exhibited regulating effects on inflammation and autoimmunity but had only limited impact on the oxidative stress damage in DN. Recent studies showed that interleukin-22 (IL-22) could inhibit mitochondrial damage and inflammatory response. Thus, the cytokine IL-22 was first fused to anti-IL-17A antibody for endowing the antibody with the anti-hyperglycemia and anti-inflammation activity. Our study demonstrated that the fusion molecule, anti-IL17A/IL22 fusion protein, could not only lead to the increase of M1 macrophages and the decrease of M2 macrophages, further improving the immune microenvironment, but also prevent the loss of mitochondrial membrane potential by reducing the production of ROS in murine DN model. In addition, the fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways, further synergistically restraining the production of NLRP3, thus suppressing the inflammatory response and playing beneficial effect on slowing down the progression of DN. In conclusion, our findings demonstrated that the bifunctional IL-17A antibody and IL-22 fusion protein were of great benefit to DN, which highlighted a potential therapeutic strategy. KEY POINTS: • Anti-IL17A/IL22 fusion protein could improve the immune microenvironment and reduce the production of ROS. • Anti-IL17A/IL22 fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways and then restrain the activation of NLRP3.

Background and aimProtein-energy wasting (PEW) is critically associated with the reduced quality of life and poor prognosis of hemodialysis patients. However, the diagnosis criteria of PEW are complex, characterized by difficulty in estimating dietary intake and assessing muscle mass loss objectively. We performed a cross-sectional study in hemodialysis patients to propose a novel PEW prediction model.Materials and methodsA total of 380 patients who underwent maintenance hemodialysis were enrolled in this cross-sectional study. The data were analyzed with univariate and multivariable logistic regression to identify influencing factors of PEW. The PEW prediction model was presented as a nomogram by using the results of logistic regression. Furthermore, receiver operating characteristic (ROC) and decision curve analysis (DCA) were used to test the prediction and discrimination ability of the novel model.ResultsBinary logistic regression was used to identify four independent influencing factors, namely, sex (P = 0.03), triglycerides (P = 0.009), vitamin D (P = 0.029), and NT-proBNP (P = 0.029). The nomogram was applied to display the value of each influencing factor contributed to PEW. Then, we built a novel prediction model of PEW (model 3) by combining these four independent variables with part of the International Society of Renal Nutrition and Metabolism (ISRNM) diagnostic criteria including albumin, total cholesterol, and BMI, while the ISRNM diagnostic criteria served as model 1 and model 2. ROC analysis of model 3 showed that the area under the curve was 0.851 (95%CI: 0.799–0.904), and there was no significant difference between model 3 and model 1 or model 2 (all P > 0.05). DCA revealed that the novel prediction model resulted in clinical net benefit as well as the other two models.ConclusionIn this research, we proposed a novel PEW prediction model, which could effectively identify PEW in hemodialysis patients and was more convenient and objective than traditional diagnostic criteria.

Oxalate-induced crystalline kidney injury is one of the most common types of crystalline nephropathy. Unfortunately, there is no effective treatment to reduce the deposition of calcium oxalate crystals and alleviate kidney damage. Thus, proactive therapeutic is urgently needed to alleviate the suffering it causes to patient. Here, we investigated whether IL-22 exerted nephroprotective effects to sodium oxalate-mediated kidney damage and its potential mechanism. Crystalline kidney injury models were developed in vitro and in vivo that was often observed in clinic. We provided evidence that IL-22 could effectively decrease the accumulation of ROS and mitochondrial damage in cell and animal models and reduce the death of TECs. Moreover, IL-22 decreased the expression of the NLRP3 inflammasome and mature IL-1β in renal tissue induced by sodium oxalate. Further studies confirmed that IL-22 could play an anti-inflammatory role by reducing the levels of cytokines such as IL-1β, IL-18, and TNF-α in serum. In conclusion, our study confirmed that IL-22 has protective effects on sodium oxalate-induced crystalline kidney injury by reducing the production of ROS, protecting mitochondrial membrane potential, and inhibiting the inflammatory response. Therefore, IL-22 may play a potential preventive role in sodium oxalate-induced acute renal injury. KEY POINTS: • IL-22 could reduce sodium oxalate-mediated cytotoxicity and ameliorate renal injury. • IL-22 could alleviate oxidative stress and mitochondrial dysfunction induced by sodium oxalate. • IL-22 could inhibit inflammatory response of renal injury caused by sodium oxalate.

正>病例资料患者,女,50岁。2018年2月15日患者无明显诱因出现双下肢及颜面水肿,至当地镇医院就诊,多次查尿蛋白均为（2+）,遂于2018年2月28日至启东市人民医院就诊,查血肌酐（serum creatinine,Scr）48μmol/L,白蛋白（albumin,Alb）25 g/L,碱性磷酸酶（alkaline phosphatase,ALP）1073U/L,谷氨酰转肽酶（γ-glutamyl transpeptadase,γ-GT）1304U/L,丙氨酸转氨酶（alanine aminotransferase,ALT）144U/L,冬氨酸氨基转移酶（aspartate aminotransferase,AST）200 U/L,总胆固醇（total cholesterol,TC）17.09 mmol/L,

Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro . Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1β, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-β signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.

AbstractKidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end‐stage renal disease (ESTD). Interleukin‐22 (IL‐22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here, we first provide evidence that IL‐22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL‐22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL‐22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL‐22 are certificated in cisplatin‐induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL‐22 on kidneys and highlight the therapeutic opportunities of IL‐22 and the involved metabolic regulators in various kidney diseases.

Acetaminophen (APAP) overdose can lead to acute, severe kidney injury, which has recently attracted considerable attention among researchers and clinicians. Unfortunately, there are no well-established treatments for APAP-induced renal injury, and the molecular mechanism of APAP-induced kidney injury is still unclear. Herein, we explored the protective effects of interleukin (IL)-22 on APAP-induced renal injury and the underlying molecular basis. We found that IL-22 could significantly alleviate the accumulation of reactive oxygen species (ROS) and ameliorate mitochondrial dysfunction, reducing APAP-induced renal tubular epithelial cell (TEC) death in vitro and in vivo. Furthermore, IL-22 could downregulate the APAP-induced NLRP3 inflammasome activation and mature IL-1β release in kidney injury. Additionally, the APAP-mediated upregulation of the serum levels of IL-18, TNF-α, IL-6, and IL-1β was obviously decreased, suggesting IL-22 has inhibitory effects on inflammatory responses. Conclusively, our study demonstrated that IL-22 exerted ameliorative effects on APAP-induced kidney injury by alleviating mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that IL-22 represents a potential therapeutic approach to treat APAP-induced kidney injury. KEY POINTS: • IL-22 could ameliorate APAP that triggered oxidative stress and mitochondrial dysfunction. • IL-22 could reduce APAP that caused inflammatory responses. Graphical abstract.

Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.

Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan-metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient cellular internalization. Furthermore, CDPIA also demonstrated a unique superiority in endosomal escape capacity and satisfactory biocompatibility as well as predominant liver accumulation. Most importantly, CDPIA distinctly alleviated hepatic steatosis, restored insulin sensitivity, and improved metabolic syndrome in high-fat-diet-fed mice model. This liver-targeted delivery of IL-22 activated STAT3/Erk1/2 and Nrf2/SOD1 signaling transductions as well as modulated lipid-metabolism-related gene expression. These findings altogether demonstrated that the polymetformin and penetratin-based hybrid nanoparticles could be exploited as a novel safe and efficient strategy for the improvement of NAFLD.

Inhibitors targeting VEGF and VEGFR are commonly used in the clinic, but only a subset of patients could benefit from these inhibitors and the efficacy was limited by multiple relapse mechanisms. In this work, we aimed to investigate the role of innate immune response in anti-angiogenic therapy and explore efficient therapeutic strategies to enhance efficacy of anti-angiogenic therapy against non-small cell lung cancer (NSCLC). Three NSCLC tumor models with responses to VEGF inhibitors were designed to determine innate immune-related underpinnings of resistance to anti-angiogenic therapy. Immunofluorescence staining, fluorescence-activated cell sorting and immunoblot analysis were employed to reveal the expression of immune checkpoint regulator CD47 in refractory NSCLC. Metastatic xenograft models and VEGFR1-SIRPα fusion protein were applied to evaluate the therapeutic effect of simultaneous disruption of angiogenetic axis and CD47-SIRPα axis. Up-regulation of an innate immunosuppressive pathway, CD47, the ligand of the negative immune checkpoint regulator SIRPα (signal regulatory protein alpha), was observed in NSCLC tumors during anti-angiogenic therapy. Further studies revealed that CD47 upregulation in refractory lung tumor models was mediated by TNF-α/NF-κB1 signal pathway. Targeting CD47 could trigger macrophage-mediated elimination of the relapsed NSCLC cells, eliciting synergistic anti-tumor effect. Moreover, simultaneously targeting VEGF and CD47 by VEGFR1-SIRPα fusion protein induced macrophages infiltration and sensitized NSCLC to angiogenesis inhibitors and CD47 blockade. Our research provided evidence that CD47 blockade could sensitize NSCLC to anti-angiogenic therapy and potentiate its anti-tumor effects by enhancing macrophage infiltration and tumor cell destruction, providing novel therapeutics for NSCLC by disrupting CD47/SIRPα interaction and angiogenetic axis.

Aristolochic acid nephropathy (AAN), as a rapidly progressive interstitial nephropathy due to excessive ingestion of aristolochia herbal medications, has recently raised considerable concerns among clinicians and researchers as its underlying pathogenic mechanisms are largely unclear. In the current study, we identified NLRP3 inflammasome activation as a novel pathological mechanism of AAN. We found that NLRP3 inflammasome was aberrantly activated both in vivo and in vitro after AA exposure. Blockade of IL-1β and NLRP3 inflammasome activation by IL-1Ra significantly attenuated renal tubular injury and function loss in AA-induced nephropathy. Moreover, NLRP3 or Caspase-1 deficiency protected against renal injury in the mouse model of acute AAN, suggesting that the NLRP3 signaling pathway was probably involved in the pathogenesis of AAN. We also found that administration of IL-22 could markedly attenuate renal tubular injury in AAN. Notably, IL-22 intervention significantly alleviated renal fibrosis and dysfunction in AA-induced nephropathy. Furthermore, IL-22 largely inhibited renal activation of NLRP3 inflammasome in AA-induced nephropathy. These results indicated that IL-22 ameliorated renal tubular injury in AAN through suppression of NLRP3 inflammasome activation. In summary, this study identified renal activation of NLRP3 inflammasome as a novel mechanism underlying the pathogenesis of AAN, thus providing a potential therapeutic strategy for AAN based on suppression of NLRP3 inflammasome activation.

肠道微生态作为肠黏膜生物屏障的重要组成部分,保护肠道免于病原菌的侵入,辅助营养吸收.肠道微生态失调参与多种慢性疾病,如糖尿病、心血管疾病.近年来一些研究证实肠道微生态和慢性肾病存在联系[1-3],而肠道微生态与糖尿病肾病(DKD)之间的研究较少,因此我们将通过阐述肠道微生态和糖尿病、慢性肾病的关系,探讨肠道微生态与DKD之间的联系,并基于肠道微生态寻找治疗DKD的新方法.

BackgroundDiabetic nephropathy (DN), the leading cause of end-stage renal disease, is acknowledged as an independent risk factor for cardiovascular disease, which underlines the urgent need for new medications to DN. Dihydroquercetin (DHQ), an important natural dihydroflavone, exerts significant antioxidant, anti-inflammatory, and antifibrotic properties, but its effects on DN have not been investigated yet.PurposeWe aimed to explore the kidney protection effects of DHQ on DN rats induced by high-fat diet/streptozotocin in vivo and the underlying mechanisms of DHQ on renal cells including HBZY-1 and HK2 exposed to high glucose in vitro.MethodsMajor biochemical indexes were measured including urine microalbumin, fasting serum glucose, serum levels of creatinine, total cholesterol and low density lipoprotein cholesterol. Renal histologic sections were stained with hematoxylin-eosin, periodic acid-Schiff and Masson. The cell proliferation was assessed by MTT assay. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay and laser scanning confocal microscope. Expression of all proteins was examined by western-blot.ResultsIn high-fat diet/streptozotocin-induced DN rats, DHQ at the dose of 100 mg/kg/day significantly attenuated the increasing urine microalbumin excretion, hyperglycemia and lipid metabolism disorders, and mitigated renal histopathological lesions. In in vitro studies, DHQ significantly suppressed cell proliferation and the excessive ROS generation, and alleviated the activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and the expression of renal fibrosis-associated proteins in renal cells exposed to high glucose.ConclusionThe results revealed that DHQ possesses kidney protection effects including attenuating urine microalbumin excretion, hyperglycemia and lipid metabolism disorders, and mitigating renal histopathological lesions on DN, and one of the possible renal-protective mechanisms is suppressing ROS and NLRP3 inflammasome.

糖尿病肾病(diabetic nephropathy,DN)是终末期肾脏病的主要病因之一,且与心血管发病率、病死率升高密切相关.目前DN的治疗方法主要包括严格控制血糖、降低血压、使用肾素-血管紧张素-醛固酮系统阻断剂减少尿蛋白.然而这些只是对症治疗,目前还未发现专门针对DN的有效治疗方法.本文阐述了一些与DN发病机制相关的生物分子如胰高血糖素样肽-1(GLP-1)、整合素αVβ3、内皮素A(ETA)、趋化因子受体2(CCR2)等,并探讨了这些分子在DN发病机制中的作用及其临床研究进展.

Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-β1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1β in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL-22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1β pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN.