Diabetes-induced Renal Dysfunction Research Articles

Smooth Muscle-Specific Knockout of LRRC8A Anion Channels Improves Vasodilation in Renal Arteries from Diabetic Mice

Leucine Rich Repeat Containing 8 (LRRC8) family proteins (LRRC8A, B, C, D and E) comprise volume-regulated anion channels (VRACs). We previously have shown that knockout (KO) or block of LRRC8A anion channel attenuates reactive oxygen species (ROS) production by Nox1, impairs TNFα-induced inflammation, and increases vascular relaxation in mesenteric arteries. These changes are associated with reduced RhoA activation. Diabetic (db/db−/−) mice have previously been shown to develop vascular dysfunction that is characterized by increased ROS production and enhanced RhoA activation. Diabetic nephropathy causes chronic renal disease and can lead to end-stage renal failure. Oxidative stress plays a role in both the initiation and progression of this process. We hypothesized that LRRC8A KO would protect vascular function in db/db−/− mice and promote vascular relaxation in renal arteries. Smooth-muscle specific LRRC8A KO mice were created in a db/db−/− background. Renal arteries were isolated from db/db−/− WT and db/db−/− LRRC8A KO mice vascular contraction and relaxation were measured. Contractile responses to phenylephrine (PE) were unaltered in LRRC8A KO compared to WT vessels. However, both endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) relaxation were increased in LRRC8A KO compared to WT rings that were contracted with PE (Emax ACh: WT 76.8 ± 5.5 vs. KO 92.2 ± 3.3 %, LogEC50 SNP: WT -7.6 ± 0.14 vs. KO -8.4 ± 0.14, n = 4-5, * p<0.05). These data demonstrate preserved vasodilation in smooth muscle-specific LRRC8A KO blood vessels. This may lead to increased renal blood flow in the setting of db/db−/−-related diabetes. Ongoing work will determine if improved vasodilation is associated with preserved renal function in these animals. If so, VRAC inhibition may provide a novel therapeutic approach to the prevention and treatment of diabetes-induced renal dysfunction. This work was supported by DK132948 and HL160975. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses

Diabetic kidney disease (DKD) is a common diabetic vascular complication affecting nearly 40% of patients with diabetes. The lack of efficacious therapy for DKD necessitates the in-depth investigation of the molecular mechanisms underlying the pathogenesis and progression of DKD, which remain incompletely understood. Here, we discovered that the expression of USP25, a deubiquitinating enzyme, was significantly upregulated in the kidney of diabetic mice. Ablation of USP25 had no influence on glycemic control in type 1 diabetes but significantly aggravated diabetes-induced renal dysfunction and fibrosis by exacerbating inflammation in the kidney. In DKD, USP25 was mainly expressed in glomerular mesangial cells and kidney-infiltrating macrophages. Upon stimulation with advanced glycation end-products (AGEs), USP25 markedly inhibited the production of proinflammatory cytokines in these two cell populations by downregulating AGEs-induced activation of NF-κB and MAPK pathways. Mechanistically, USP25 interacted with TRAF6 and inhibited its K63 polyubiquitination induced by AGEs. Collectively, these findings identify USP25 as a novel regulator of DKD.

Sclareol ameliorates hyperglycemia-induced renal injury through inhibiting the MAPK/NF-κB signaling pathway.

Diabetic nephropathy (DN) represents the most serious complication of diabetes. Previous studies have shown that the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) are linked to inflammation in the development of DN. Sclareol, a natural diterpene compound, has beneficial effects on inflammation. Thus, we hypothesized that sclareol might prevent DN via anti-inflammatory actions. This study aimed to investigate the actions of sclareol in the progression of DN, and explored the related molecular mechanism. Sclareol treatment significantly alleviated renal dysfunction, fibrosis, and inflammatory cytokine levels in a dose-dependent manner in diabetic mice. Moreover, sclareol inhibited the activations of MAPKs and NF-κB in diabetic kidney tissues. The therapeutic effects of sclareol were confirmed under high levels of glucose in SV40 cells, and sclareol prevented high glucose-induced fibrosis and inflammatory responses, which was largely driven by MAPKs and NF-κB inhibitions. In particular, MAPKs inhibitors mixture could suppress the NF-κB pathway and release of inflammatory cytokines that sclareol was involved in. In conclusion, sclareol has benefits for diabetes-induced renal dysfunction, which was partially associated with amelioration of fibrosis and inflammation via mediation of the MAPK/NF-κB signaling pathway. Sclareol may be a promising agent for preventing the progression of DN.

RNA-Seq analysis reveals critical transcriptome changes caused by sodium butyrate in DN mouse models.

Diabetic nephropathy (DN)—a common complication of diabetes—is the primary cause of end-stage renal disease. Sodium butyrate (NaB) is a short-chain fatty acid (SCFA) that is a metabolic product of intestinal bacterium, and its protective effect on the kidney has been reported in cases of DN. However, its underlying mechanism remains unclear. The aim of the present study was to investigate the effect of NaB on globe transcriptome changes in DN. In our study, 8-week-old male db/db mice suffering from DN were randomly divided into two groups: the DN+NaB group (DN mice treated with NaB, 5 g/kg/day) and the DN group (DN mice treated with saline). Further, normal db/m mice were used as the normal control (NC) group. The blood glucose, body weight, urinary microalbumin and urinary creatinine of mice were measured for all three groups. Whole-transcriptome analysis was performed by RNA sequencing (RNA-Seq) to evaluate the profiling of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs). Bioinformatics analysis was performed to predict the potential NaB-related lncRNAs and genes in DN. The expressions of lncRNAs and mRNAs were tested using the quantitative real-time polymerase chain reactions (qRT-PCRs) in renal tissues and mesangial cells treated with NaB. The results of the present study demonstrated that NaB ameliorated renal dysfunction in DN mice. Moreover, RNA-Seq results identified that some lncRNAs and mRNAs were reversely changed in the DN+NaB group in comparison to those in the DN group. Additionally, the integrated co-expression networks of NaB-related lncRNAs revealed that these lncRNAs interacted with 155 key mRNAs. Furthermore, the co-expression network of inflammation-related lncRNAs and mRNAs demonstrated that those reversed lncRNAs and mRNAs also play essential roles in the inflammatory response. In summary, the present study suggests that NaB ameliorates diabetes-induced renal dysfunction and regulates transcriptome changes in DN.

Pectin-Lyase-Modified Ginseng Extract and Ginsenoside Rd Inhibits High Glucose-Induced ROS Production in Mesangial Cells and Prevents Renal Dysfunction in db/db Mice.

Diabetes increases the incidence rate of chronic renal disease. Pectin-lyase-modified ginseng (GS-E3D), with enhanced ginsenoside Rd content, has been newly developed. In this study, renal protective roles of GS-E3D in type-2 diabetic db/db mice were investigated. The generation of reactive oxygen species (ROS) induced by high glucose (25 mM) was reduced by ES-E3D (75%) and ginsenoside Rd (60%). Diabetic db/db mice received 100 or 250 mg/kg/day of GS-E3D daily via oral gavage for 6 weeks. Albuminuria and urinary 8-hydroxy-2′-deoxyguanosine (8-OhdG, an oxidative stress marker) levels were increased in db/db mice and the levels recovered after GS-E3D treatment. In renal tissues, TUNEL-positive cells were decreased after GS-E3D treatment, and the increased apoptosis-related protein expressions were restored after GS-E3D treatment. Therefore, GS-E3D has a potent protective role in diabetes-induced renal dysfunction through antioxidative and antiapoptotic activities. These results may help patients to select a dietary supplement for diabetes when experiencing renal dysfunction.

Renoprotective effects of Tilianin in diabetic rats through modulation of oxidative stress via Nrf2-Keap1 pathway and inflammation via TLR4/MAPK/NF-κB pathways

The present study was undertaken to assess the protective effects of Tilianin (TN) on type-2 diabetes-induced renal dysfunction in experimental rats. Diabetes was induced by injecting Nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg) by i.p. and then the rats were treated with TN (10 and 20 mg/kg) daily by oral gavage for 28 days. TN treatment significantly decreases the BUN, creatinine, 24-hour urinary protein, urea, uric acid, and albumin protein levels. The protein of expression of Nrf2, NQO1, and HO-1 was augmented while the expression of Keap-1 decreased significantly. TN also reduces the oxidative/nitrosative status by lowering MDA content, NO, and MPO levels. TN exerted anti-inflammatory effects by suppressing TLR4/NF-κB/MAPK signaling cascades and inhibiting MyD88, TRAF6, IκBα, p38MAPK, JNK, and ERK2 in the diabetic rats. Histopathological findings supported the biochemical and molecular results. The results showed that TN modulated Nrf2-Keap1 and TLR4/MAPK/NF-κB signaling pathways and provided significant protection against diabetes-induced renal dysfunction.

Diabetic nephropathy execrates epithelial-to-mesenchymal transition (EMT) via miR-2467-3p/Twist1 pathway

Although diabetic nephropathy (DN) is induced by a complicate interplay of multiple factors, the underlying mechanisms remain poorly characterized, even the treatment. Herein, we show that both of DN patients and STZ-induced type 1 diabetic rat exhibit the reduction both of urinary and circulating miR-2467-3p. We identify a negative correlation between miR-2467-3p levels and renal dysfunction. Administration of miR-2467-3p prevents diabetes-induced renal dysfunction and represses renal fibrosis in STZ-induced type 1 diabetic rats. Conversely, anti-miR-2467 overexpression exacerbates renal dysfunction and fibrosis in STZ-induced rats. In diabetic condition, the reduction of miR-2467-3p promotes expression of Twist1, inducing epithelial-to-mesenchymal transition (EMT), resulting in renal fibrosis and kidney dysfunction. Together, our study presents miR-2467/Twist1/EMT as a regulatory axis of renal dysfunction in DN.

Ethyl Vanillin Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting Oxidative Stress and Apoptosis.

Diabetes-induced oxidative stress and apoptosis is regarded as a critical role in the pathogenesis of diabetic nephropathy (DN). Treating diabetes-induced kidney damage and renal dysfunction has been thought a promising therapeutic option to attenuate the development and progression of DN. In this study, we investigated the renoprotective effect of ethyl vanillin (EVA), an active analogue of vanillin isolated from vanilla beans, on streptozotocin- (STZ-) induced rat renal injury model and high glucose-induced NRK-52E cell model. The EVA treatment could strongly improve the deterioration of renal function and kidney cell apoptosis in vivo and in vitro. Moreover, treating with EVA significantly decreased the level of MDA and reactive oxygen species (ROS) and stabilized antioxidant enzyme system in response to oxidative stress by enhancing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro. Furthermore, EVA also markedly suppressed cleaved caspase-3, Bax, and nuclear transcription factor erythroid 2-related factor (Nrf2) expression in STZ-induced rats. Therefore, these results of our investigation provided that EVA might protect against kidney injury in DN by inhibiting oxidative stress and cell apoptosis.

Histone demethylase UTX is a therapeutic target for diabetic kidney disease.

Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid-induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK-J4 treatment showed the opposite effects. We found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end-stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di- and tri-methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK-J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

Protective effects of plant-derived natural products on renal complications.

Diabetic nephropathy is the leading cause of renal failure worldwide. This debilitating disorder has several underlying pathophysiologic mechanisms, and therefore a variety of pharmacologic agents have been developed to prevent or treat diabetic nephropathy; however, synthetic drugs may possess unfavorable side effects. In response to this, the global use of herbal-based pharmacologic agents is increasing among diabetic patients. Numerous studies have reported therapeutic benefits of herbal-based compounds against diabetes-induced renal dysfunction. These agents can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress, inflammation, apoptosis, necrosis, and nitric oxide deprivation that lead to vascular injuries. In the current study, we have reviewed the beneficial properties of the most common herbal agents used in renal complications and diabetic nephropathy.

Narrative review of the effects of antidiabetic drugs on albuminuria.

Diabetes mellitus is the most prevalent metabolic disorder worldwide. Glycemic control is the main focus of antidiabetic therapy. However, there are data suggesting that some antidiabetic drugs may have intrinsic beneficial renal effects and protect against the development and progression of albuminuria, thus minimizing the risk of diabetic nephropathy. These pharmacological agents can suppress upstream molecular pathways involved in the pathophysiology of diabetes-induced renal dysfunction such as oxidative stress, inflammatory responses, and apoptosis. In this narrative review, the pathophysiology of albuminuria in patients with diabetic nephropathy is discussed. Furthermore, the renoprotective effects of antidiabetic drugs, focusing on albuminuria, are reviewed.

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus.

AIMTo investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity.METHODSChronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment.RESULTSCoagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes (SREBP-1C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation (CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-α. Coagonist treatment reduced expression of inflammatory (TNF-α, MCP-1, and MMP-9) and pro-fibrotic (TGF-β, COL1A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSIONCoagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy.

c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125's protection against DN. To test the role of NRF2 in SP600125's effect, streptozotocin-induced C57BL/6 wild-type (WT) and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125's protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced Keap1 expression.

GS-E3D, a new pectin lyase-modified red ginseng extract, inhibited diabetes-related renal dysfunction in streptozotocin-induced diabetic rats

BackgroundGS-E3D is a newly developed pectin lyase-modified red ginseng extract. The purpose of this study was to investigate the therapeutic effects of GS-E3D on diabetes-related renal dysfunction in streptozotocin-induced diabetic rats.MethodGS-E3D (25, 50, and 100 mg/kg body weight per day) was administered for 6 weeks. The levels of blood glucose and hemoglobin A1c, and of urinary albumin, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and advanced glycation end-products (AGEs) were determined. Kidney histopathology, renal accumulation of AGEs, and expression of α-smooth muscle actin (α-SMA) were also examined.ResultsAdministration of GS-E3D for 6 weeks reduced urinary levels of albumin, 8-OHdG, and AGEs in diabetic rats. Mesangial expansion, renal accumulation of AGEs, and enhanced α-SMA expression were significantly inhibited by GS-E3D treatment. Oral administration of GS-E3D dose-dependently improved all symptoms of diabetic nephropathy by inhibiting renal accumulation of AGEs and oxidative stress.ConclusionThe results of this study indicate that the use of GS-E3D as a food supplement may provide effective treatment of diabetes-induced renal dysfunction.

Role of HSP60 (HSPD1) in diabetes‐induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress

Because underlying mechanisms of diabetic nephropathy/tubulopathy remained poorly understood, we aimed to define a key protein involving in hyperglycemia-induced renal tubular dysfunction. All altered renal proteins identified from previous large-scale proteome studies were subjected to global protein network analysis, which revealed heat shock protein 60 (HSP60, also known as HSPD1) as the central node of protein-protein interactions. Functional validation was performed using small interfering RNA (siRNA) to knock down HSP60 (siHSP60). At 48 h after exposure to high glucose (HG) (25 mM), Madin-Darby canine kidney (MDCK) renal tubular cells transfected with controlled siRNA (siControl) had significantly increased level of HSP60 compared to normal glucose (NG) (5.5 mM), whereas siHSP60-transfected cells showed a dramatically decreased HSP60 level. siHSP60 modestly increased intracellular protein aggregates in both NG and HG conditions. Luciferin-luciferase assay showed that HG modestly increased intracellular ATP, and siHSP60 further enhanced such an increase. OxyBlot assay showed significantly increased level of oxidized proteins in HG-treated siControl-transfected cells, whereas siHSP60 caused marked increase of oxidized proteins under the NG condition. However, the siHSP60-induced accumulation of oxidized proteins was abolished by HG. In summary, our data demonstrated that HSP60 plays roles in regulation of intracellular protein aggregation, ATP production, and oxidative stress in renal tubular cells. Its involvement in HG-induced tubular cell dysfunction was most likely via regulation of intracellular ATP production.-Aluksanasuwan, S., Sueksakit, K., Fong-ngern, K., Thongboonkerd, V. Role of HSP60 (HSPD1) in diabetes-induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress.

Prevention of Streptozotocin-Induced Diabetic Nephropathy by MG132: Possible Roles of Nrf2 and IκB.

Our previous study showed that proteasomal inhibitor MG132 can prevent diabetic nephropathy (DN) along with upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The present study was to investigate whether MG132 can prevent DN in wild-type and Nrf2-KO mice. Type 1 diabetes was induced in wild-type and Nrf2-KO mice by multiple low doses of streptozotocin. Two weeks after streptozotocin injection, both wild-type and Nrf2-KO mice were randomly divided into four groups: control, MG132, DM, and DM/MG132. MG132 (10 μg/kg/day) or vehicle was administered intraperitoneally for 4 months. Renal function, morphology, and biochemical changes were measured after 4-month treatment with MG132. MG132 treatment suppressed proteasomal activity in the two genotypes. In wild-type mice, MG132 attenuated diabetes-induced renal dysfunction, fibrosis, inflammation, and oxidative damage along with increased Nrf2 and IκB expression. Deletion of Nrf2 gene resulted in a partial, but significant attenuation of MG132 renal protection in Nrf2-KO mice compared with wild-type mice. MG132-increased IκB expression was not different between wild-type and Nrf2-KO mice. This work indicates that MG132 inhibits diabetes-increased proteasomal activity, resulting in Nrf2 and IκB upregulation and renal protection, which could be used as a strategy to prevent diabetic nephropathy.

Effects and mechanism of miR-23b on glucose-mediated epithelial-to-mesenchymal transition in diabetic nephropathy

MicroRNAs (miRNAs) play important roles in epithelial-to-mesenchymal transition (EMT). Moreover, hyperglycaemia induces damage to renal tubular epithelial cells, which may lead to EMT in diabetic nephropathy. However, the effects of miRNAs on EMT in diabetic nephropathy are poorly understood. In the present study, we found that the level of microRNA-23b (miR-23b) was significantly decreased in high glucose (HG)-induced human kidney proximal tubular epithelial cells (HK2) and in kidney tissues of db/db mice. Overexpression of miR-23b attenuated HG-induced EMT, whereas knockdown of miR-23b induced normal glucose (NG)-mediated EMT in HK2 cells. Mechanistically, miR-23b suppressed EMT in diabetic nephropathy by targeting high mobility group A2 (HMGA2), thereby repressing PI3K-AKT signalling pathway activation. Additionally, HMGA2 knockdown or inhibition of the PI3K-AKT signalling pathway with LY294002 mimicked the effects of miR-23b overexpression on HG-mediated EMT, whereas HMGA2 overexpression or activation of the PI3K-AKT signalling pathway with BpV prevented the effects of miR-23b on HG-mediated EMT. We also confirmed that overexpression of miR-23b alleviated EMT, decreased the expression levels of EMT-related genes, ameliorated renal morphology, glycogen accumulation, fibrotic responses and improved renal functions in db/db mice. Taken together, we showed for the first time that miR-23b acts as a suppressor of EMT in diabetic nephropathy through repressing PI3K-AKT signalling pathway activation by targeting HMGA2, which maybe a potential therapeutic target for diabetes-induced renal dysfunction.

Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation

Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation.

Optimal conditions of LDR to protect the kidney from diabetes: Exposure to 12.5 mGy X-rays for 8 weeks efficiently protects the kidney from diabetes

AimsWe reported the attenuation of diabetes-induced renal dysfunction by exposure to multiple low-dose radiation (LDR) at 25mGy every other day by suppressing renal oxidative damage. We here explored the optimal conditions of LDR to protect the kidney from diabetes. Main methodsMale C57BL/6J mice with type 1 diabetes were induced with multiple injections of low-dose streptozotocin. Diabetic mice received whole body X-irradiation at a dose of 12.5, 25 or 50mGy every other day for either 4 or 8weeks. Age-matched normal mice were similarly irradiated at the dose of 25mGy for 4 or 8weeks. The renal function and histopathological changes were examined at the 4th and 8th weeks of the study. Key findingsDiabetes induced renal dysfunction is shown by the decreased creatinine and increased microalbumin in the urine. Renal oxidative damage, detected by protein nitration and lipid oxidation, and remodeling, reflected by increased expression of connective tissue growth factor, collagen IV and fibronectin, were significantly increased in diabetic mice. All these renal pathological and function changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens, among which, however, exposure to LDR at 12.5mGy for 8weeks provided the best protective effect on the kidney of diabetic mice. SignificanceOur results suggest that whole-body LDR at 12.5mGy every other day for 8weeks is the optimal condition of LDR to protect the kidney from diabetes.

WldSameliorates renal injury in a type 1 diabetic mouse model

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide. The purpose of this study is to investigate whether the Wld(S) (slow Wallerian degeneration; also known as Wld) gene plays a renoprotective role during the progression of DN. Diabetes was induced in 8-wk-old male wild-type (WT) and C57BL/Wld(S) mice by streptozotocin (STZ) injection. Blood and urinary variables including blood glucose, glycated hemoglobin (GHb), insulin, urea nitrogen, and albumin/creatinine ratio were assessed 4, 7, and 14 wk after STZ injection. Periodic acid-Schiff staining, Masson staining, and silver staining were performed for renal pathological analyses. In addition, the renal ultrastructure was observed by electron microscope. The activities of p38 and ERK signaling in renal cortical tissues were evaluated by Western blotting. NAD(+)/NADH ratio and NADPH oxidase activity were also measured. Moreover, the expressions of TNF-α, IL-1, and IL-6 were examined. We provide experimental evidence demonstrating that the Wld(S) gene is expressed in kidney cells and protects against the early stage of diabetes-induced renal dysfunction and extracellular matrix accumulation through delaying the reduction of the NAD(+)/NADH ratio, inhibiting the activation of p38 and ERK signaling, and suppressing oxidative stress as evidenced by the decreased NADPH oxidase activity and lower expression of TNF-α, IL-1, and IL-6.