Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression.

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.

Vascular calcification in CKD: New insights into its mechanisms.

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD) and contributes to an increased risk of cardiovascular morbidity and mortality. However, effective therapies are still unavailable at present. It has been well established that VC associated with CKD is not a passive process of calcium phosphate deposition, but an actively regulated and cell-mediated process that shares many similarities with bone formation. Additionally, numerous studies have suggested that CKD patients have specific risk factors and contributors to the development of VC, such as hyperphosphatemia, uremic toxins, oxidative stress and inflammation. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in CKD-related VC, many questions remain unanswered. Moreover, studies from the past decade have demonstrated that epigenetic modifications abnormalities, such as DNA methylation, histone modifications and noncoding RNAs, play an important role in the regulation of VC. This review seeks to provide an overview of the pathophysiological and molecular mechanisms of VC associated with CKD, mainly focusing on the involvement of epigenetic modifications in the initiation and progression of uremic VC, with the aim to develop promising therapies for CKD-related cardiovascular events in the future.

P53 regulates mitochondrial biogenesis via transcriptionally induction of mitochondrial ribosomal protein L12.

The well-documented tumor suppressor p53 is also a major stress response factor for its diverse regulation on cellular energetics. However, the effect of p53 on mitochondrial biogenesis, which plays a predominant role in response to the elevated energy demands, appears to be pleiotropic in various conditions and has not reached agreement. Mitochondrial ribosomal protein L12 (MRPL12), reported as a bi-functional protein for its roles in both mitochondrial ribosomes and transcriptional complexes, is a core regulatory component in mitochondrial biogenesis. Here we proved that MRPL12 is transcriptionally regulated by p53. Furthermore, the p53/MRPL12 regulation of mitochondria is part of the signaling pathway that maintains the basal mitochondrial content and positively coordinates the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) in response to metabolic perturbation. Since p53 serves as the'Guardian of the Genome', our findings may revealed a new mechanism underlying the conditions when more ATP is warranted to maintain the genome integrity and cell survival. Therefore the pharmacological intervention or metabolic modulation (e.g., through fasting or exercise) of the p53/MRPL12 pathway promises to be a therapeutic approach that can safeguard health.

Association between glomerular C4d deposition, proteinuria, and disease severity in children with IgA nephropathy.

BACKGROUND: C4d may be used as a marker to evaluate the condition and prognosis of adults with IgA nephropathy, but there have been few studies of children with IgA nephropathy. METHODS: C4d immunohistochemical staining was performed on samples from children with IgA nephropathy with C1q-negative immunofluorescence. The clinical and pathological treatment and prognostic characteristics of children in the C4d-positive and -negative groups were compared. RESULTS: A total of sixty-five children with IgA nephropathy were included in the study and were followed up for an average of 37 months. C4d was mainly deposited along the capillary loops. The urinary protein-to-creatinine ratio (UPCR) in the C4d-positive group was significantly higher than that in the C4d-negative group (3.97 vs. 0.81, P < 0.001), and the average integrated optical density value of each child was positively correlated with the UPCR (r = 0.441, P < 0.001). There was a significant difference in the proportions of children with mesangial hypercellularity (M1) (68.97% vs. 44.44%, P = 0.048) and segmental glomerulosclerosis (S1) (65.52% vs. 33.33%, P = 0.010) between the C4d-positive group and the C4d-negative group. The proportion of children who received immunosuppressants in the C4d-positive group was higher than that in the C4d-negative group (86.21% vs. 36.11%, P < 0.001). There was no significant difference in the proportion of children developing kidney failure between the two groups. CONCLUSION: C4d was found to be associated with proteinuria, segmental lesions, and immunosuppressant treatment. Activation of the lectin pathway may reflect the severity of clinical and pathological manifestations of IgA nephropathy in children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Targeting tissue-resident memory CD8+ T cells in the kidney is a potential therapeutic strategy to ameliorate podocyte injury and glomerulosclerosis.

Although tissue-resident-memory T (TRM) cells, a recently identified non-circulating memory T cell population, play a crucial role in mediating local immune responses and protect against pathogens upon local reinfection, the composition, effector function, and specificity of TRM cells in the kidney and their relevance for chronic kidney disease remain unknown. In this study, we found that renal tissue displayed high abundance of tissue-resident lymphocytes, and the proportion of CD8+ TRM cells was significantly increased in the kidney from patients and mice with focal segmental glomerulosclerosis (FSGS), diabetic kidney disease (DKD), and lupus nephritis (LN). Mechanistically, IL-15 significantly promoted CD8+ TRM cell formation and activation, thereby promoting podocyte injury and glomerulosclerosis. Interestingly, Sparsentan, the dual angiotensin II (Ang II) receptor and endothelin type A receptor antagonist, can also reduce TRM cell responses by intervening IL-15 signaling, exploring its new pharmacological functions. Mechanistically, Sparsentan inhibited Ang II or endothelin-1 (ET-1)-mediated IL-15 signaling, thereby further regulating renal CD8+ TRM cell fates. Collectively, our studies provide direct evidence for the pivotal role of renal CD8+ TRM cells in podocyte injury and further strengthen that targeting TRM cells represents a novel therapeutic strategy for patients with glomerular diseases.

Hypoxia induced-disruption of lncRNA TUG1/PRC2 interaction impairs human trophoblast invasion through epigenetically activating Nodal/ALK7 signalling.

Inadequate trophoblastic invasion is considered as one of hallmarks of preeclampsia (PE), which is characterized by newly onset of hypertension (>140/90 mmHg) and proteinuria (>300 mg in a 24-h urine) after 20 weeks of gestation. Accumulating evidence has indicated that long noncoding RNAs are aberrantly expressed in PE, whereas detailed mechanisms are unknown. In the present study, we showed that lncRNA Taurine upregulated 1 (TUG1) were downregulated in preeclamptic placenta and in HTR8/SVneo cells under hypoxic conditions, together with reduced enhancer of zeste homolog2 (EZH2) and embryonic ectoderm development (EED) expression, major components of polycomb repressive complex 2 (PRC2), as well as activation of Nodal/ALK7 signalling pathway. Mechanistically, we found that TUG1 bound to PRC2 (EZH2/EED) in HTR8/SVneo cells and weakened TUG1/PRC2 interplay was correlated with upregulation of Nodal expression via decreasing H3K27me3 mark at the promoter region of Nodal gene under hypoxic conditions. And activation of Nodal signalling prohibited trophoblast invasion via reducing MMP2 levels. Overexpression of TUG1 or EZH2 significantly attenuated hypoxia-induced reduction of trophoblastic invasiveness via negative modulating Nodal/ALK7 signalling and rescuing expression of its downstream target MMP2. These investigations might provide some evidence for novel mechanisms responsible for inadequate trophoblastic invasion and might shed some light on identifying future therapeutic targets for PE.

Myeloid-derived growth factor deficiency exacerbates mitotic catastrophe of podocytes in glomerular disease.

Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering the mitotic phase causes podocyte mitotic catastrophe, thereby leading to podocyte death and glomerular injury. Myeloid-derived growth factor (MYDGF) is a novel secreted protein and plays an important role in the regulation of cardiovascular function. However, whether MYDGF is expressed in kidney parenchymal cells and whether it has biological functions in the kidney remain unknown. Here, we found that MYDGF was expressed in kidney parenchymal cells and was significantly reduced in podocytes from mice with models of focal segmental glomerulosclerosis and diabetic kidney disease. Podocyte-specific deletion of Mydgf in mice exacerbated podocyte injury and proteinuria in both disease models. Functionally, MYDGF protected podocytes against mitotic catastrophe by reducing accumulation of podocytes in the S phase, a portion of the cell cycle in which DNA is replicated. Mechanistically, MYDGF regulates the expression of the transcription factor RUNX2 which mediates some MYDGF effects. Importantly, a significant reduction of MYDGF was found in glomeruli from patients with glomerular disease due to focal segmental glomerulosclerosis and diabetic kidney disease and the level of MYDGF was correlated with glomerular filtration rate, serum creatinine and podocyte loss. Thus, our studies indicate that MYDGF may be an attractive therapeutic target for glomerular disease.

CLEC14A protects against podocyte injury in mice with adriamycin nephropathy.

Podocyte injury is a major determinant of focal segmental glomerular sclerosis (FSGS) and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance for the treatment of FSGS. CLEC14A is a single-pass transmembrane glycoprotein belonging to the vascular expressed C-type lectin family. CLEC14A is found to be expressed in vascular endothelial cells during embryogenesis and is also implicated in tumor angiogenesis. However, the current understanding of the biological functions of CLEC14A in podocyte is very limited. In this study, we found that CLEC14A was expressed in podocyte and protected against podocyte injury in mice with Adriamycin (ADR)-induced FSGS. First, we observed that CLEC14A was downregulated in mice with ADR nephropathy and renal biopsies from individuals with FSGS and other forms of podocytopathies. Moreover, CLEC14A deficiency exacerbated podocyte injury and proteinuria in mice with ADR nephropathy accompanied by enhanced inflammatory cell infiltration and inflammatory responses. In vitro, overexpression of CLEC14A in podocyte had pleiotropic protective actions, including anti-inflammatory and anti-apoptosis effects. Mechanistically, CLEC14A inhibited high-mobility group box 1 protein (HMGB1) release, at least in part by directly binding HMGB1, and suppressed HMGB1-mediated signaling, including NF-κB signaling and early growth response protein 1 (EGR1) signaling. Taken together, our findings provide new insights into the pivotal role of CLEC14A in maintaining podocyte function, indicating that CLEC14A may be an innovative therapeutic target in FSGS.

Role of SIK1 in the transition of acute kidney injury into chronic kidney disease.

BACKGROUND: Acute kidney injury (AKI), with a high morbidity and mortality, is recognized as a risk factor for chronic kidney disease (CKD). AKI-CKD transition has been regarded as one of the most pressing unmet needs in renal diseases. Recently, studies have showed that salt inducible kinase 1 (SIK1) plays a role in epithelial-mesenchymal transition (EMT) and inflammation, which are the hallmarks of AKI-CKD transition. However, whether SIK1 is involved in AKI-CKD transition and by what mechanism it regulates AKI-CKD transition remains unknown. METHODS: We firstly detected the expression of SIK1 in kidney tissues of AKI patients and AKI mice by immunohistochemistry staining, and then we established Aristolochic acid (AA)-induced AKI-CKD transition model in C57BL/6 mice and HK2 cells. Subsequently, we performed immunohistochemistry staining, ELISA, real-time PCR, Western blot, immunofluorescence staining and Transwell assay to explore the role and underlying mechanism of SIK1 on AKI-CKD transition. RESULTS: The expression of SIK1 was down-regulated in AKI patients, AKI mice, AA-induced AKI-CKD transition mice, and HK2 cells. Functional analysis revealed that overexpression of SIK1 alleviated AA-induced AKI-CKD transition and HK2 cells injury in vivo and in vitro. Mechanistically, we demonstrated that SIK1 mediated AA-induced AKI-CKD transition by regulating WNT/ß-catenin signaling, the canonical pathway involved in EMT, inflammation and renal fibrosis. In addition, we discovered that inhibition of WNT/ß-catenin pathway and its downstream transcription factor Twist1 ameliorated HK2 cells injury, delaying the progression of AKI-CKD transition. CONCLUSIONS: Our study demonstrated, for the first time, a protective role of SIK1 in AKI-CKD transition by regulating WNT/ß-catenin signaling pathway and its downstream transcription factor Twist1, which will provide novel insights into the prevention and treatment AKI-CKD transition in the future.

USP36 protects proximal tubule cells from ischemic injury by stabilizing c-Myc and SOD2.

Acute kidney injury (AKI) is a progressive renal injury with high morbidity and mortality, however, the mechanism is far from being clarified and effective clinical interventions are lacking. USP36 is a deubiquitination enzyme involved in a variety of cellular biological processes, but its involvement in renal cell apoptosis and kidney disease is largely unknown. In the present study, we confirmed the decreased expression of USP36 both in vivo in mouse and human AKI samples and in vitro ischemic human renal proximal tubular cells, which are extremely sensitive to the damage of ischemic injury. Importantly, we found that overexpression of USP36 markedly decreased ischemia-induced apoptosis and oxidative stress in HK-2 cells, which was accompanied by elevated c-Myc and SOD2 protein levels with alleviated ischemia-induced ubiquitination of both proteins. Our findings revealed a novel role of USP36 in inhibiting apoptosis of human renal tubular cells induced by ischemia, and provided a potential therapeutic target for AKI treatment.

Analysis of clinical features and pathology of serum HBsAg positive glomerulonephritis.

To analyze the relationship between the factors related to the occurrence of HBV-GN and serum HBsAg-positive glomerulonephritis. A total of 56 patients were enrolled in the present study. All enrolled cases were divided into two groups according to whether HBsAg and/or HBcAg was present in renal kidney tissue: patients with Hepatitis B virus-associated nephritis (HBV-GN group, 30 cases) and patients with hepatitis B virus-combined nephritis (HBV-CG group, 26 cases). We sought to analyze the differences in clinical features and pathological characteristics in both groups. The rate of HBeAg positivity in the HBV-GN group was considerably increased in the HBV-CG group (P < 0.05), and the number of patients with HBsAg+HBeAg+HBcAb+ in the HBV-GN group was considerably increased in the HBV-CG group (21 cases vs 10 cases) (P < 0.05). Moreover, the number of MCD patients diagnosed by renal biopsy in the HBV-GN group was reduced compared with the HBV-CG group (1 case vs 7 cases) (P < 0.05). HBV infection and high-virus proliferation status were closely related with HBV-GN.

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F-actin re-organization via activating p38 in response to ox-LDL.

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet-induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder-related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c-Src, Rho GTPase and mitogen-activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low-density lipoprotein (ox-LDL) triggered hyper-phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re-arrangement of F-actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre-treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper-activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox-LDL damaged podocytes in a FAK/p38-dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia-related podocyte damage and proteinuria.

LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose-induced podocyte injury via its interplay with ß-catenin.

Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a long non-coding RNA, broadly expressed in mammalian tissues including kidney and up-regulated in a variety of cancer cells. To date, its functions in podocytes are largely unknown. ß-catenin is a key mediator in the canonical and non-canonical Wnt signalling pathway; its aberrant expression promotes podocyte malfunction and albuminuria, and contributes to kidney fibrosis. In this study, we found that MALAT1 levels were increased in kidney cortices from C57BL/6 mice with streptozocin (STZ)-induced diabetic nephropathy, and dynamically regulated in cultured mouse podocytes stimulated with high glucose, which showed a trend from rise to decline. The decline of MALAT1 levels was accompanied with ß-catenin translocation to the nuclei and enhanced expression of serine/arginine splicing factor 1 (SRSF1), a MALAT1 RNA-binding protein. Further we showed early interference with MALAT1 siRNA partially restored podocytes function and prohibited ß-catenin nuclear accumulation and SRSF1 overexpression. Intriguingly, we showed that ß-catenin was involved in MALAT1 transcription by binding to the promotor region of MALAT1; ß-catenin knock-down also decreased MALAT1 levels, suggesting a novel feedback regulation between MALAT1 and ß-catenin. Notably, ß-catenin deletion had limited effects on SRSF1 expression, demonstrating ß-catenin might serve as a downstream signal of SRSF1. These findings provided evidence for a pivotal role of MALAT1 in diabetic nephropathy and high glucose-induced podocyte damage.

The spectrum of biopsy-proven secondary glomerular diseases: A cross-sectional study in China
.

AIMS: The distribution of the spectrum of chronic kidney disease (CKD) has been found to vary with time. Limited information is available regarding the changing spectrum of secondary glomerular diseases (SGDs). To further investigate changes in the spectrum of SGDs, we performed a cross-sectional study. METHODS: From June 2010 to May 2015, 5,935 patients from 37 hospitals in Shandong Province were involved in this study. The study was divided into five periods according to 1-year intervals. The patients were divided into four age groups. RESULTS: Of the 5,935 patients with qualified specimens, 1,038 (17.5%) were diagnosed with a SGD. Lupus nephritis (LN) (27.6%) was the most frequently identified SGD, followed by Henoch-Schönlein purpura glomerulonephritis (HSPN) (21.7%) and diabetic nephropathy (DN) (21.6%). The prevalence rate of DN demonstrated an increasing trend, and this condition became the leading cause of renal biopsy in period 3 (29.3%). The proportion of patients with hepatitis B virus-associated nephritis (HBVAN) decreased from 14.7% in period 2 to 5.1% in period 5 (p < 0.001). The proportion of patients with amyloidosis nephropathy (AN) increased from 2.2% in period 1 to 7.0% in period 5 (p = 0.088). The prevalence rate of DN was 0.6% in pediatric patients and 40.7% in elderly patients (p < 0.001). CONCLUSIONS: In our study, SGD was the second leading cause of renal biopsy. The distribution of the spectrum of SGD varied with time and age. Given the possibility of a detection bias, larger prospective cohort studies are needed in the future.
.

Increasing prevalence of membranous nephropathy in patients with primary glomerular diseases: A cross-sectional study in China.

AIM: Primary glomerular disease (PGD) remains the most common renal disease in China. A limited number of single centre studies show that the frequency of membranous nephropathy (MN) has increased; however, IgA nephropathy (IgAN) is still the most common PGD. To the best of our knowledge, there has been no multi-centre study in China that has explored the changes in PGD spectrum. To further investigate the changes in renal histopathological spectrum, we performed the cross-sectional study. METHOD: From June 2010 to May 2015, 5935 patients from 37 hospitals in Shandong Province were involved in this retrospective study. The study was divided into five periods according to 1-year intervals. The patients were divided into four age groups (≤18 years, 19-44 years, 45-59 years and ≥60 years). RESULT: Among the 5935 qualified specimens, 4855 (81.8%) were diagnosed with PGD. MN (43.3%) became the most common PGD instead of IgA (34.1%) (P < 0.001). The frequency of MN was increased from 30.7% in period 1 to 53.5% in period 5 (P < 0.001). The prevalence of MN tended to increase in every age section. IgA was the main cause of PGD in periods 1 and 2; however, its proportion decreased significantly from 41.8% in period 2 to 25.2% in period 5 (P < 0.001). CONCLUSION: Primary glomerular disease remains the most common renal disease in our study. For the first time, this cross-sectional study suggests that MN, in place of IgAN, has grown to be the first leading pathological type of PGD.

Organic Cation Transporter 2 Overexpression May Confer an Increased Risk of Gentamicin-Induced Nephrotoxicity.

Nephrotoxicity is a relevant limitation of gentamicin, and obese patients have an increased risk for gentamicin-induced kidney injury. This damage is thought to depend on the accumulation of the drug in the renal cortex. Obese rats showed substantially higher levels of gentamicin in the kidney than did lean animals. This study characterized the role of organic cation transporters (OCTs) in gentamicin transport and elucidated their possible contribution in the increased renal accumulation of gentamicin in obesity. The mRNA and protein expression levels of the organic cation transporters Oct2 (Slc22a2) and Oct3 (Slc22a3) were increased in kidney samples from obese mice fed a high-fat diet. Similarly, OCT2 (∼2-fold) and OCT3 (∼3-fold) showed increased protein expression in the kidneys of obese patients compared with those of nonobese individuals. Using HEK293 cells overexpressing the different OCTs, human OCT2 was found to transport [(3)H]gentamicin with unique sigmoidal kinetics typical of homotropic positive cooperativity (autoactivation). In mouse primary proximal tubular cells, [(3)H]gentamicin uptake was reduced by approximately 40% when the cells were coincubated with the OCT2 substrate metformin. The basolateral localization of OCT2 suggests that gentamicin can enter proximal tubular cells from the blood side, probably as part of a slow tubular secretion process that may influence intracellular drug concentrations and exposure time. Increased expression of OCT2 may explain the higher accumulation of gentamicin, thereby conferring an increased risk of renal toxicity in obese patients.

Leptin promotes endothelial dysfunction in chronic kidney disease through AKT/GSK3ß and ß-catenin signals.

Endothelial dysfunction (ED) is a well-recognized instigator of cardiovascular diseases and develops in chronic kidney disease (CKD) with high rate. Recent studies have implicated that leptin is associated with endothelial dysfunction. We investigated the relationship between leptin and markers of ED in CKD patients and how leptin contributed to endothelial damage. 140 CKD patients and 140 healthy subjects were studied. Serum leptin levels were significantly higher in CKD than in controls and displayed significantly positive association with the increase levels of sICAM-1 and sVCAM-1 but negative correlation with flow-mediated dilatation (FMD) reduction in patients. Our in vitro study demonstrated that leptin induced overexpression of ICAM-1 and VCAM-1, led to f-actin reorganization and vinculin assembly, increased endothelial monolayer permeability for FITC-dextran, and accelerated endothelial cell migration; these changes were markedly reversed when the cells were transfected with AKT or ß-catenin shRNA vectors. Notably, high leptin resulted in hyper-phosphorylation of AKT and GSK3ß, along with nuclear accumulation of ß-catenin. In conclusion, serum leptin was elevated in CKD patients and it might contribute to endothelial dysfunction by disarrangement of f-actin cytoskeleton via a mechanism involving the AKT/GSK3ß and ß-catenin pathway.

Chronic kidney disease: pathological and functional assessment with diffusion tensor imaging at 3T MR.

OBJECTIVE: Our objective was to evaluate pathological and functional changes in chronic kidney disease (CKD) using diffusion tensor imaging (DTI) at 3 T. METHODS: There were fifty-one patients with CKD who required biopsy and 19 healthy volunteers who were examined using DTI at 3 T. The mean values of fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) were obtained from the renal parenchyma (cortex and medulla). Correlations between imaging results and the estimated glomerular filtration rate (eGFR), as well as pathological damage (glomerular lesion and tubulointerstitial injury), were evaluated. RESULTS: The renal cortical FA was significantly lower than the medullary in both normal and affected kidneys (p < 0.001). The parenchymal FA was significantly lower in patients than healthy controls, regardless of whether eGFR was reduced. There were positive correlations between eGFR and FA (cortex, r = 0.689, p = 0.000; and medulla, r = 0.696, p = 0.000), and between eGFR and ADC (cortex, r = 0.310, p = 0.017; and medulla, r = 0.356, p = 0.010). Negative correlations were found between FA and the glomerular lesion (cortex, r = -0.499, p = 0.000; and medulla, r = -0.530, p = 0.000), and between FA and tubulointerstitial injury (cortex, r = -0.631, p = 0.000; and medulla, r = -0.724, p = 0.000). CONCLUSION: DTI is valuable for noninvasive assessment of renal function and pathology in patients with CKD. A decrease in FA could identify the glomerular lesions, tubulointerstitial injuries, and eGFR.

Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy.

Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-ß (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.