Anping Xu

Ribosomal protein S19 is a novel therapeutic agent in inflammatory kidney disease.

RPS19 (ribosomal protein S19), a component of the 40S small ribosomal subunit, has recently been identified to bind the pro-inflammatory cytokine macrophage MIF (migration inhibitory factor). In vitro experiments identify RPS19 as the first endogenous MIF inhibitor by blocking the binding of MIF to its receptor CD74 and MIF functions on monocyte adherence to endothelial cells. In the present study, we sought to establish whether recombinant RPS19 can exert anti-inflammatory effects in a mouse model of anti-GBM (glomerular basement membrane) GN (glomerulonephritis) in which MIF is known to play an important role. Accelerated anti-GBM GN was induced in C57BL/6J mice by immunization with sheep IgG followed 5 days later by administration of sheep anti-mouse GBM serum. Groups of eight mice were treated once daily by intraperitoneal injection with 6 mg of RPS19/kg of body weight or an irrelevant control protein (human secretoglobin 2A1), or received no treatment, from day 0 until being killed on day 10. Mice that received control or no treatment developed severe crescentic anti-GBM disease on day 10 with increased serum creatinine, declined creatinine clearance and increased proteinuria. These changes were associated with up-regulation of MIF and its receptor CD74 activation of ERK (extracellular-signal-regulated kinase) and NF-κB (nuclear factor κB) signalling, prominent macrophage and T-cell infiltration, as well as up-regulation of Th1 [T-bet and IFNγ (interferon γ)] and Th17 [STAT3 (signal transducer and activator of transcription 3) and IL (interleukin)-17A] as well as IL-1β and TNFα (tumour necrosis factor α). In contrast, RPS19 treatment largely prevented the development of glomerular crescents and glomerular necrosis, and prevented renal dysfunction and proteinuria (all P<0.001). Of note, RPS19 blocked up-regulation of MIF and CD74 and inactivated ERK and NF-κB signalling, thereby inhibiting macrophage and T-cell infiltration, Th1 and Th17 responses and up-regulation of pro-inflammatory cytokines (all P<0.01). These results demonstrate that RPS19 is a potent anti-inflammatory agent, which appears to work primarily by inhibiting MIF signalling.

Factors that can minimize bleeding complications after renal biopsy

Renal biopsy is a very important diagnostic tool in the evaluation of renal diseases. However, bleeding remains to be one of the most serious complications in this procedure. Many new techniques have been improved to make it safer. The risk factors and predictors of bleeding after percutaneous renal biopsy have been extensively reported in many literatures, and generally speaking, the common risk factors for renal biopsy complications focus on hypertension, high serum creatinine, bleeding diatheses, amyloidosis, advanced age, gender and so on. Our primary purpose of this review is to summarize current measures in recent years literature aiming at minimizing the bleeding complication after the renal biopsy, including the drug application before and after renal biopsy, operation details in percutaneous renal biopsies, nursing and close monitoring after the biopsy and other kinds of biopsy methods.

C-reactive protein and ageing

Increasing evidence shows that C‐reactive protein (CRP) is not only an inflammatory biomarker but also an important risk factor associated with ageing‐related diseases including cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Recent studies have demonstrated that CRP is pathogenic in a number of diseases including hypertensive cardiovascular and kidney complications, diabetic nephropathy, and acute and chronic kidney diseases. It is well known that CRP binds its receptor, CD32/CD64, to induce the process of inflammation by activating the NF‐κB signalling pathway. In addition, CRP mediates tissue fibrosis in a number of cardiovascular and kidney diseases by activating TGF‐β/Smad signalling via TGF‐β1‐dependent and independent mechanisms. Furthermore, CRP is able to activate mTOR signalling in the diabetic conditions. Our recent studies also revealed that CRP impairs cell regeneration by causing the G1 cell cycle arrest and promotes ageing via a Smad3‐dependent p21/p27 mechanism. In this review, we discuss the roles of CRP in ageing, with a focus on its function and mechanisms in physiological or “healthy” ageing, in ageing‐related diseases, and in cell signalling.

Protective effect of Fenofibrate in renal ischemia reperfusion injury: Involved in suppressing kinase 2 (JAK2)/transcription 3 (STAT3)/p53 signaling activation.

OBJECTIVE Renal ischemia reperfusion (I/R) injury is a common reason of acute kidney injury. Apoptosis play an important role in the IRI. Fenofibrate, one of agonist Peroxisome proliferator-activated receptor-alpha (PPARα) has the effect of anti-apoptosis. This study was to explore the effect of Fenofibrate on renal ischemia reperfusion injury and its mechanism. MATERIALS AND METHODS IRI was induced by bilateral renal ischemia for 45 min followed by reperfusion for 24h. Eighteen male C57BL/6 mice were randomly divided into three groups: Sham group (Sham), IRI group (IRI), I/R-Fenofibrate group (FEN). Fenofibrate was injected at 45 min before renal ischemia. Renal histology, function, and the expression of Bax, Bcl-2, Bcl-xl p21, p53, Caspase3, CytC, p-JAK2, p-STAT3 and p-PPAR-α were assessed. RESULTS Fenofibrate precondition can significantly alleviate the renal dysfunction, the pathological change, up-regulate the expression of p-PPAR-α, Bcl-2, Bcl-xl, Caspase3 and down-regulate the expression of p-JAK2, p-STAT3, p53, p21, CytC and Bax induced by renal IR injury. CONCLUSION Fenofibrate precondition can protect mice against IRI by suppressing p53-mediating apoptosis which was associated with inhibiting JAK2/STAT3 signaling activation though further activating PPAR-α. Our findings suggest that Fenofibrate could be useful for preventing IR-induced renal injury.

TGF-β-Induced CD8+CD103+ Regulatory T Cells Show Potent Therapeutic Effect on Chronic Graft-versus-Host Disease Lupus by Suppressing B Cells

Lupus nephritis is one of most severe complications of systemic erythematosus lupus and current approaches are not curative for lupus nephritis. Although CD4+Foxp3+ regulatory T cells (Treg) are crucial for prevention of autoimmunity, the therapeutic effect of these cells on lupus nephritis is not satisfactory. We previously reported that CD8+CD103+ Treg induced ex vivo with TGF-β1 and IL-2 (CD8+CD103+ iTreg), regardless of Foxp3 expression, displayed potent immunosuppressive effect on Th cell response and had therapeutic effect on Th cell-mediated colitis. Here, we tested whether CD8+CD103+ iTreg can ameliorate lupus nephritis and determined potential molecular mechanisms. Adoptive transfer of CD8+CD103+ iTreg but not control cells to chronic graft-versus-host disease with a typical lupus syndrome showed decreased levels of autoantibodies and proteinuria, reduced renal pathological lesions, lowered renal deposition of IgG/C3, and improved survival. CD8+CD103+ iTreg cells suppressed not only T helper cells but also B cell responses directly that may involve in both TGF-β and IL-10 signals. Using RNA-seq, we demonstrated CD8+CD103+ iTreg have its own unique expression profiles of transcription factors. Thus, current study has identified and extended the target cells of CD8+CD103+ iTreg and provided a possible application of this new iTreg subset on lupus nephritis and other autoimmune diseases.

Smad7 protects against Acute Kidney Injury by rescuing tubular epithelial cells from the G1 cell cycle arrest

Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-β/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-β/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI.

Predictors of Vitamin D Deficiency in Predialysis Patients with Stage 3–5 Chronic Kidney Diseases in Southern China

Objective: Vitamin D status and risk factors of Vitamin D deficiency in chronic kidney disease (CKD) patients in China have been seldom reported before. In this study, we aim to investigate serum 25-hydroxyvitamin D [25(OH)D] status and find the predictors of Vitamin D deficiency in predialysis patients with Stage 3–5 CKDs in Southern China. Methods: In this retrospective cross-sectional study, hospitalized predialysis patients who were diagnosed of Stage 3–5 CKD and had taken measurement of serum 25(OH)D in a single center from January 2014 to June 2015 were included. Patients were divided into Vitamin D deficiency group and nondeficiency group depending on the cutoff serum 25(OH)D value of 37 nmol/L. Clinical and biochemical parameters were collected and evaluated for predictors of Vitamin D deficiency by logistic regression. Results: One hundred and fifty-two patients were included in this study, of which 87 (57.2%) were in Vitamin D insufficiency state while 60 (39.5%) were in Vitamin D deficiency state. Serum 25(OH)D levels of patients in Stage 4 and Stage 5 CKD were lower than that of patients in Stage 3 CKD (P = 0.002). It was discovered that female gender (odds ratio [OR] = 3.674; 95% confidence interval [CI], 1.607–8.396; P = 0.002), serum albumin level <30.0 g/L (OR = 6.816; 95% CI, 2.634–17.633; P < 0.001), and estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 (OR = 4.761; 95% CI, 1.353–16.754; P = 0.015) were independent predictors of Vitamin D deficiency. Conclusions: Vitamin D insufficiency and deficiency are common in predialysis patients with Stage 3–5 CKD in Southern China. Female gender, hypoalbuminemia with serum albumin level <30.0 g/L, and severe damaged renal function with eGFR <30 ml/min/1.73 m2 are independent predictors of Vitamin D deficiency in predialysis patients with Stage 3–5 CKD.