Faculty Opinions recommendation of CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease.

2021 ◽  
Author(s):  
Volker Vallon
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Ace Inhibition ◽  
Tubular Damage ◽  
Diabetic Kidney

Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease

2018 ◽  
Vol 132 (22) ◽  
pp. 2407-2422 ◽  
Author(s):  
Wenxia Yang ◽  
Ying Luo ◽  
Shikun Yang ◽  
Mengru Zeng ◽  
Shumin Zhang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Lipid Accumulation ◽  
Diabetic Kidney Disease ◽  
Mononuclear Cells ◽  
Regulatory Element ◽  
Tubular Damage ◽  
Tubular Injury ◽  
Diabetic Kidney ◽  
Tnf Α ◽  
Significant Difference

Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes II–III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl-β-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-α (TNF-α) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-α levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-α expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD.

scholarly journals The Role of Podocytes and Podocyte-Associated Biomarkers in Diagnosis and Treatment of Diabetic Kidney Disease

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Igor Kravets ◽  
Sandeep K Mallipattu
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Public Health Problem ◽  
Diabetic Patients ◽  
Tubular Damage ◽  
Preventative Care ◽  
Important Public Health Problem ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Filtration Barrier

Abstract Diabetic kidney disease (DKD) is an important public health problem. Podocyte injury is a central event in the mechanism of DKD development. Podocytes are terminally differentiated, highly specialized glomerular visceral epithelial cells critical for the maintenance of the glomerular filtration barrier. Although potential mechanisms by which diabetic milieu contributes to irreversible loss of podocytes have been described, identification of markers that prognosticate either the development of DKD or the progression to end-stage kidney disease (ESKD) have only recently made it to the forefront. Currently, the most common marker of early DKD is microalbuminuria; however, this marker has significant limitations: not all diabetic patients with microalbuminuria will progress to ESKD and as many as 30% of patients with DKD have normal urine albumin levels. Several novel biomarkers indicating glomerular or tubular damage precede microalbuminuria, suggesting that the latter develops when significant kidney injury has already occurred. Because podocyte injury plays a key role in DKD pathogenesis, identification of markers of early podocyte injury or loss may play an important role in the early diagnosis of DKD. Such biomarkers in the urine include podocyte-released microparticles as well as expression of podocyte-specific markers. Here, we review the mechanisms by which podocyte injury contributes to DKD as well as key markers that have been recently implicated in the development and/or progression of DKD and might serve to identify individuals that require earlier preventative care and treatment in order to slow the progression to ESKD.

scholarly journals Urinary Neutrophil Gelatinase-Associated Lipocalin Is Complementary to Albuminuria in Diagnosis of Early-Stage Diabetic Kidney Disease in Type 2 Diabetes

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Agnieszka Gala-Błądzińska ◽  
Paulina Dumnicka ◽  
Beata Kuśnierz-Cabala ◽  
Katarzyna Rybak ◽  
Ryszard Drożdż ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Control Group ◽  
Tubular Damage ◽  
Diabetic Kidney ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Neutrophil Gelatinase

Background. Two clinical phenotypes of diabetic kidney disease (DKD) have been reported, that is, with or without increased albuminuria. The aim of study was to assess the usefulness of urinary neutrophil gelatinase-associated lipocalin (uNGAL) for the early diagnosis of DKD in the type 2 diabetes mellitus (T2DM). Methods. The study group consisted of 123 patients with T2DM (mean age 62 ± 14 years), with urine albumin/creatinine ratio (uACR) < 300 mg/g and eGFR ≥ 60 ml/min/1.73 m2. The control group included 22 nondiabetic patients with comparable age, sex, and comorbidities. uNGAL, albumin, and creatinine were measured in the first morning urine samples. uACR and uNGAL/creatinine ratios (uNCR) were calculated. Results. In the control group, maximum uNCR was 39.64 µg/g. In T2DM group, 24 patients (20%) had higher results, with the maximum value of 378.6 µg/g. Among patients with uNCR > 39.64 µg/g, 13 (54%) did not have markedly increased albuminuria. Women with T2DM had higher uNCR than men (p<0.001), without difference in uACR (p=0.09). uNCR in T2DM patients correlated significantly with HbA1c. Sex, total cholesterol, and uACR were independent predictors of uNCR above 39.64 µg/g. Conclusions. Increased uNGAL and uNCR may indicate early tubular damage, associated with dyslipidemia and worse diabetes control, especially in females with T2DM.

scholarly journals Streptozotocin induces alpha-2u globulin nephropathy in male rats during diabetic kidney disease

2021 ◽  
Author(s):  
Kanchana Kengkoom ◽  
Wannee Angkhasirisap ◽  
Tapanee Kanjanapruthipong ◽  
Rongdej Tungtrakanpoung ◽  
Khwanchanok Tuentam ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Model ◽  
Wistar Rat ◽  
Immunogold Labelling ◽  
Male Rats ◽  
Tubular Damage ◽  
Diabetic Kidney ◽  
Clinical Illness ◽  
Renal Tubular

Abstract Background: Alpha-2u globulin nephropathy mainly shows toxicological pathology only in male rats induced by certain chemicals and drugs, such as levamisole (antiparasitic and anticancer drugs). Streptozotocin (STZ) is also an anticancer-antibiotic agent that has been used for decades to induce a diabetic kidney disease model in rodents. The purpose of this study is to determine if STZ causes alpha-2u globulin nephropathy in male rats during an advanced stage of diabetic kidney disease.Methods: To test this hypothesis, the present study used a male diabetic Wistar rat model with 45 mg/kg of STZ injected intraperitoneally. Hyperglycaemic rats were divided into 2 groups: with and without alpha-2u globulin deposition in proximal tubule. Alpha-2u globulin nephropathy was examined by histopathological and electron microscope studies. Water absorption and filtration capacities (via aquaporin [AQP]-1, -2, -4 and -5) and mitochondrial function (through haloacid dehalogenase-like hydrolase domain-containing protein [HDHD]-3 and NADH-ubiquinone oxidoreductase 75 kDa subunit [NDUFS]-1 proteins) were determined using immunohistochemistry, immunofluorescence and immunogold labelling techniques.Results: More than 80% of severe clinical illness rats induced by STZ injection simultaneously exhibited alpha-2u globulin nephropathy with mitochondrial degeneration and filtration apparatus especially pedicels impairment. They also showed significantly upregulated AQP-1, -2, -4 and -5, HDHD-3 and NDUFS-1 compared with those of the rats without alpha-2u globulin nephropathy.Conclusions: STZ-induced alpha-2u globulin nephropathy during diabetic kidney disease in association with deterioration of pedicels, renal tubular damage with adaptation and mitochondrial driven apoptosis.

scholarly journals Streptozotocin induces alpha-2u globulin nephropathy in male rats during diabetic kidney disease

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Kanchana Kengkoom ◽  
Wannee Angkhasirisap ◽  
Tapanee Kanjanapruthipong ◽  
Rongdej Tungtrakanpoung ◽  
Khwanchanok Tuentam ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Model ◽  
Wistar Rat ◽  
Male Rats ◽  
Tubular Damage ◽  
Diabetic Kidney ◽  
Filtration Apparatus ◽  
Clinical Illness ◽  
Renal Tubular

Abstract Background Alpha-2u globulin nephropathy mainly shows toxicological pathology only in male rats induced by certain chemicals and drugs, such as levamisole (antiparasitic and anticancer drugs). Streptozotocin (STZ) is also an anticancer-antibiotic agent that has been used for decades to induce a diabetic kidney disease model in rodents. The purpose of this study is to determine if STZ causes alpha-2u globulin nephropathy in male rats during an advanced stage of diabetic kidney disease. Alpha-2u globulin nephropathy, water absorption and filtration capacities (via aquaporin [AQP]-1, − 2, − 4 and − 5) and mitochondrial function (through haloacid dehalogenase-like hydrolase domain-containing protein [HDHD]-3 and NADH-ubiquinone oxidoreductase 75 kDa subunit [NDUFS]-1 proteins) were examined in STZ-induced diabetic Wistar rat model. Results More than 80% of severe clinical illness rats induced by STZ injection simultaneously exhibited alpha-2u globulin nephropathy with mitochondrial degeneration and filtration apparatus especially pedicels impairment. They also showed significantly upregulated AQP-1, − 2, − 4 and − 5, HDHD-3 and NDUFS-1 compared with those of the rats without alpha-2u globulin nephropathy. Conclusions STZ-induced alpha-2u globulin nephropathy during diabetic kidney disease in association with deterioration of pedicels, renal tubular damage with adaptation and mitochondrial driven apoptosis.

CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease

2021 ◽  
pp. ASN.2021040431
Author(s):  
Khurrum Shahzad ◽  
Sameen Fatima ◽  
Moh'd Al-Dabet ◽  
Ihsan Gadi ◽  
Hamzah Khawaja ◽  
...  
Keyword(s):  
Cell Death ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Human Kidney ◽  
Locked Nucleic Acid ◽  
Tubular Damage ◽  
Kidney Cells ◽  
Diabetic Kidney ◽  
Chop Expression ◽  
Factor C

Background: Maladaptive ER stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell death-promoting transcription factor C/EBP homologous protein (CHOP). We determined whether therapy with locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorates experimental DKD. Methods: Following an in vivo dose-escalation study, we determined the efficacy of CHOPASO in the early and later stages of experimental DKD (8- or 16-week-old db/db mice, respectively) alone or in combination with an angiotensin-converting enzyme inhibitor (ACEi). Renal functional parameters and morphological analyses were used to determine the effects. Renal gene expression profiling was conducted to determine differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. Results: CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. A significantly larger number of genes and disease pathways were affected by CHOP-ASO, including reduced Slc5a2 (sodium-glucose transport protein 2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented cell death of human kidney cells in vitro. Conclusions: The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi in particular at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.

scholarly journals Urinary Extracellular Vesicles as a Source of NGAL for Diabetic Kidney Disease Evaluation in Children and Adolescents With Type 1 Diabetes Mellitus

2022 ◽  
Vol 12 ◽  
Author(s):  
Francisca Ugarte ◽  
Daniela Santapau ◽  
Vivian Gallardo ◽  
Carolina Garfias ◽  
Anahí Yizmeyián ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Type 1 Diabetes Mellitus ◽  
Extracellular Vesicles ◽  
Diabetic Kidney Disease ◽  
Tubular Damage ◽  
Activated T Cells ◽  
Diabetic Kidney

BackgroundTubular damage has a role in Diabetic Kidney Disease (DKD). We evaluated the early tubulointerstitial damage biomarkers in type-1 Diabetes Mellitus (T1DM) pediatric participants and studied the correlation with classical DKD parameters.MethodsThirty-four T1DM and fifteen healthy participants were enrolled. Clinical and biochemical parameters [Glomerular filtration Rate (GFR), microalbuminuria (MAU), albumin/creatinine ratio (ACR), and glycated hemoglobin A1c (HbA1c)] were evaluated. Neutrophil gelatinase-associated lipocalin (NGAL), Hypoxia-inducible Factor-1α (HIF-1α), and Nuclear Factor of Activated T-cells-5 (NFAT5) levels were studied in the supernatant (S) and the exosome-like extracellular vesicles (E) fraction from urine samples.ResultsIn the T1DM, 12% had MAU &gt;20 mg/L, 6% ACR &gt;30 mg/g, and 88% had eGFR &gt;140 ml/min/1.72 m2. NGAL in the S (NGAL-S) or E (NGAL-E) fraction was not detectable in the control. The NGAL-E was more frequent (p = 0.040) and higher (p = 0.002) than NGAL-S in T1DM. The T1DM participants with positive NGAL had higher age (p = 0.03), T1DM evolution (p = 0.03), and serum creatinine (p = 0.003) than negative NGAL. The NGAL-E correlated positively with tanner stage (p = 0.0036), the median levels of HbA1c before enrollment (p = 0.045) and was independent of ACR, MAU, and HbA1c at the enrollment. NFAT5 and HIF-1α levels were not detectable in T1DM or control.ConclusionUrinary exosome-like extracellular vesicles could be a new source of early detection of tubular injury biomarkers of DKD in T1DM patients.

scholarly journals Normoalbuminuric chronic kidney disease in diabetes

2018 ◽  
Vol 90 (10) ◽  
pp. 94-98
Author(s):  
V V Klimontov ◽  
A I Korbut
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Treatment Options ◽  
Practical Importance ◽  
Future Research ◽  
Diabetic Patients ◽  
Tubular Damage ◽  
Diabetic Kidney

Urinary albumin excretion (UAE) is widely used in clinical practice as indicator of diabetic kidney disease. According to the classical concept of the natural course of diabetic nephropathy, an increase in UAE usually precedes a decline in renal function. Meanwhile, a growing body of evidences indicates a high prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in diabetic subjects, especially among patients with type 2 diabetes. An increase in NA-CKD prevalence can be results of improved glucose, blood pressure, and lipid control, widespread use of renin-angiotensin system blockers, and smoking cessation. It was shown that NA-CKD is more prevalent among women and is associated with arterial hypertension and coronary artery disease. The renal structure in subjects with NA-CKD is more heterogeneous when compared to patients with increased albuminuria, wherein interstitial changes and arteriolosclerosis could be the principal morphological findings, while signs of glomerulopathy may be absent. The prognostic value of NA-CKD needs to be clarified. It was shown that NA-CKD increases the risk of myocardial infarction, stroke and cardiovascular death in patients with diabetes. The search for alternative diagnostic markers for detecting of diabetic kidney disease in the absence of albuminuria, is of practical importance. The evaluations of the markers of tubular damage and interstitial fibrosis, as well as proteomic approaches, are considered as perspective diagnostic and prognostic options in NA-CKD. The study of pathogenesis, pathology, clinical course of NA-CKD in diabetic patients, as well as the development of more specific diagnostic and treatment options is a challenge for future research.

scholarly journals Streptozotocin induces alpha-2u globulin nephropathy in male rats during the end-stage of diabetic kidney disease

2020 ◽  
Author(s):  
Kanchana Kengkoom ◽  
Wannee Angkhasirisap ◽  
Tapanee Kanjanapruthipong ◽  
Rongdej Tungtrakanpoung ◽  
Khwanchanok Tuentam ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Model ◽  
Wistar Rat ◽  
Immunogold Labelling ◽  
Male Rats ◽  
Tubular Damage ◽  
Diabetic Kidney ◽  
Renal Tubular ◽  
End Stage

Abstract Background Alpha-2u globulin nephropathy mainly shows toxicological pathology only in male rats induced by certain chemicals and drugs, such as levamisole (antiparasitic and anticancer drugs). Streptozotocin (STZ) is also an anticancer-antibiotic agent that has been used for decades to induce a diabetic kidney disease model in rodents. The purpose of this study is to determine if STZ causes alpha-2u globulin nephropathy in male rats during an advanced stage of diabetic kidney disease. Methods To prove this hypothesis, the present study used a male diabetic Wistar rat model with 45 mg/kg of STZ injected intraperitoneally. Hyperglycaemic rats were divided into 2 groups: with and without end-stage kidney disease. Alpha-2u globulin nephropathy was examined by histopathological and electron microscope studies. Water absorption and filtration capacities (via aquaporin [AQP]-1, -2, -4 and -5) and mitochondrial function (through haloacid dehalogenase-like hydrolase domain-containing protein [HDHD]-3 and NADH-ubiquinone oxidoreductase 75 kDa subunit [NDUFS]-1 proteins) were determined using immunohistochemistry, immunofluorescence and immunogold labelling techniques. Results More than 80% of end-stage diabetic kidney disease induced by STZ injection simultaneously exhibited alpha-2u globulin nephropathy with mitochondrial degeneration and filtration apparatus especially pedicels impairment. They also showed significantly upregulated AQP-1, -2, -4 and -5, HDHD-3 and NDUFS-1 compared with those of the rats without alpha-2u globulin nephropathy. Conclusions STZ-induced alpha-2u globulin nephropathy during end-stage diabetic kidney disease in association with deterioration of renal filtration, renal tubular damage with adaptation and mitochondrial apoptosis.

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