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TGF-β and Diabetic Nephropathy: Lessons Learned Over the Past 20 Years.
Gewin LS
(2020) Am J Med Sci 359: 70-72
MeSH Terms: Diabetic Nephropathies, History, 20th Century, History, 21st Century, Humans, Kidney, Transforming Growth Factor beta1
Added March 18, 2020
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6 MeSH Terms
Long-term outcomes in mouse models of ischemia-reperfusion-induced acute kidney injury.
Scarfe L, Menshikh A, Newton E, Zhu Y, Delgado R, Finney C, de Caestecker MP
(2019) Am J Physiol Renal Physiol 317: F1068-F1080
MeSH Terms: Acute Kidney Injury, Animals, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Disease Models, Animal, Female, Fibrosis, Kidney Function Tests, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Nephrectomy, Reperfusion Injury, Sex Characteristics, Species Specificity
Show Abstract · Added May 10, 2020
Severe acute kidney injury has a high mortality and is a risk factor for progressive chronic kidney disease. None of the potential therapies that have been identified in preclinical studies have successfully improved clinical outcomes. This failure is partly because animal models rarely reflect the complexity of human disease: most preclinical studies are short term and are commonly performed in healthy, young, male mice. Therapies that are effective in preclinical models that share common clinical features seen in patients with acute kidney injury, including genetic diversity, different sexes, and comorbidities, and evaluate long-term outcomes are more likely to predict success in the clinic. Here, we evaluated susceptibility to chronic kidney disease after ischemia-reperfusion injury with delayed nephrectomy by monitoring long-term functional and histological responses to injury. We defined conditions required to induce long-term postinjury renal dysfunction and fibrosis without increased mortality in a reproducible way and evaluate effect of mouse strains, sexes, and preexisting diabetes on these responses.
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Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes.
Li Z, Li Y, Overstreet JM, Chung S, Niu A, Fan X, Wang S, Wang Y, Zhang MZ, Harris RC
(2018) Diabetes 67: 1847-1857
MeSH Terms: Albuminuria, Animals, Biomarkers, Crosses, Genetic, Cytokines, Diabetes Mellitus, Type 2, Diabetic Nephropathies, ErbB Receptors, Erlotinib Hydrochloride, Fibrosis, Glomerulonephritis, Hypoglycemic Agents, Insulin Resistance, Kidney, Macrophages, Membrane Transport Modulators, Mice, Knockout, Mice, Mutant Strains, Nitric Oxide Synthase Type III, Oxidative Stress, Protein Kinase Inhibitors, T-Lymphocytes, Transforming Growth Factor alpha
Show Abstract · Added November 9, 2018
Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS with endothelial nitric oxide knockout [eNOS]). eNOS mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity () and transforming growth factor-α () were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both and diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity.
© 2018 by the American Diabetes Association.
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23 MeSH Terms
Assessment of renal fibrosis in murine diabetic nephropathy using quantitative magnetization transfer MRI.
Wang F, Katagiri D, Li K, Takahashi K, Wang S, Nagasaka S, Li H, Quarles CC, Zhang MZ, Shimizu A, Gore JC, Harris RC, Takahashi T
(2018) Magn Reson Med 80: 2655-2669
MeSH Terms: Animals, Diabetic Nephropathies, Fibrosis, Image Interpretation, Computer-Assisted, Kidney, Magnetic Resonance Imaging, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type III, Normal Distribution, Reproducibility of Results
Show Abstract · Added June 1, 2018
PURPOSE - Renal fibrosis is a hallmark of progressive renal disease; however, current clinical tests are insufficient for assessing renal fibrosis. Here we evaluated the utility of quantitative magnetization transfer MRI in detecting renal fibrosis in a murine model of progressive diabetic nephropathy (DN).
METHODS - The db/db eNOS-/- mice, a well-recognized model of progressive DN, and normal wild-type mice were imaged at 7T. The quantitative magnetization transfer data were collected in coronal plane using a 2D magnetization transfer prepared spoiled gradient echo sequence with a Gaussian-shaped presaturation pulse. Parameters were derived using a two-pool fitting model. A normal range of cortical pool size ratio (PSR) was defined as Mean±2SD of wild-type kidneys (N = 20). The cortical regions whose PSR values exceeded this threshold (threshold PSR) were assessed. The correlations between the PSR-based and histological (collagen IV or picrosirius red stain) fibrosis measurements were evaluated.
RESULTS - Compared with wild-type mice, moderate increases in mean PSR values and scattered clusters of high PSR region were observed in cortex of DN mouse kidneys. Abnormally high PSR regions (% area) that were detected by the threshold PSR were significantly increased in renal cortexes of DN mice. These regions progressively increased on aging and highly correlated with histological fibrosis measures, while the mean PSR values correlated much less.
CONCLUSION - Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.
© 2018 International Society for Magnetic Resonance in Medicine.
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11 MeSH Terms
Imaging mass spectrometry reveals direct albumin fragmentation within the diabetic kidney.
Grove KJ, Lareau NM, Voziyan PA, Zeng F, Harris RC, Hudson BG, Caprioli RM
(2018) Kidney Int 94: 292-302
MeSH Terms: Albumins, Albuminuria, Animals, Cathepsin D, Diabetic Nephropathies, Disease Models, Animal, Frozen Sections, Humans, Kidney Glomerulus, Kidney Tubules, Mice, Mice, Inbred C57BL, Molecular Imaging, Nitric Oxide Synthase Type III, Proteolysis, Renal Elimination, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added May 29, 2018
Albumin degradation in the renal tubules is impaired in diabetic nephropathy such that levels of the resulting albumin fragments increase with the degree of renal injury. However, the mechanism of albumin degradation is unknown. In particular, fragmentation of the endogenous native albumin has not been demonstrated in the kidney and the enzymes that may contribute to fragmentation have not been identified. To explore this we utilized matrix-assisted laser desorption/ionization imaging mass spectrometry for molecular profiling of specific renal regions without disturbing distinct tissue morphology. Changes in protein expression were measured in kidney sections of eNOSdb/db mice, a model of diabetic nephropathy, by high spatial resolution imaging allowing molecular localizations at the level of single glomeruli and tubules. Significant increases were found in the relative abundances of several albumin fragments in the kidney of the mice with diabetic nephropathy compared with control nondiabetic mice. The relative abundance of fragments detected correlated positively with the degree of nephropathy. Furthermore, specific albumin fragments accumulating in the lumen of diabetic renal tubules were identified and predicted the enzymatic action of cathepsin D based on cleavage specificity and in vitro digestions. Importantly, this was demonstrated directly in the renal tissue with the endogenous nonlabeled murine albumin. Thus, our results provide molecular insights into the mechanism of albumin degradation in diabetic nephropathy.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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17 MeSH Terms
Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control.
Li Y, Chung S, Li Z, Overstreet JM, Gagnon L, Grouix B, Leduc M, Laurin P, Zhang MZ, Harris RC
(2018) JCI Insight 3:
MeSH Terms: Acetates, Animals, Blood Glucose, Diabetic Nephropathies, Disease Models, Animal, Fatty Acids, Fibrosis, Kidney, Membrane Proteins, Mice, Receptors, Cell Surface
Show Abstract · Added May 29, 2018
Extensive kidney fibrosis occurs in several types of chronic kidney diseases. PBI-4050, a potentially novel first-in-class orally active low-molecular weight compound, has antifibrotic and antiinflammatory properties. We examined whether PBI-4050 affected the progression of diabetic nephropathy (DN) in a mouse model of accelerated type 2 diabetes and in a model of selective tubulointerstitial fibrosis. eNOS-/- db/db mice were treated with PBI-4050 from 8-20 weeks of age (early treatment) or from 16-24 weeks of age (late treatment). PBI-4050 treatment ameliorated the fasting hyperglycemia and abnormal glucose tolerance tests seen in vehicle-treated mice. In addition, PBI-4050 preserved (early treatment) or restored (late treatment) blood insulin levels and increased autophagy in islets. PBI-4050 treatment led to significant improvements in lifespan in the diabetic mice. Both early and late PBI-4050 treatment protected against progression of DN, as indicated by reduced histological glomerular injury and albuminuria, slow decline of glomerular filtration rate, and loss of podocytes. PBI-4050 inhibited kidney macrophage infiltration, oxidative stress, and TGF-β-mediated fibrotic signaling pathways, and it also protected against the development of tubulointerstitial fibrosis. To confirm a direct antiinflammatory/antifibrotic effect in the kidney, further studies with a nondiabetic model of EGFR-mediated proximal tubule activation confirmed that PBI-4050 dramatically decreased the development of the associated tubulointerstitial injury and macrophage infiltration. These studies suggest that PBI-4050 attenuates development of DN in type 2 diabetes through improvement of glycemic control and inhibition of renal TGF-β-mediated fibrotic pathways, in association with decreases in macrophage infiltration and oxidative stress.
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11 MeSH Terms
Risk of Hypoglycemia Following Hospital Discharge in Patients With Diabetes and Acute Kidney Injury.
Hung AM, Siew ED, Wilson OD, Perkins AM, Greevy RA, Horner J, Abdel-Kader K, Parr SK, Roumie CL, Griffin MR, Ikizler TA, Speroff T, Matheny ME
(2018) Diabetes Care 41: 503-512
MeSH Terms: Acute Kidney Injury, Adult, Aged, Blood Glucose, Diabetes Mellitus, Diabetic Nephropathies, Female, Glipizide, Glyburide, Humans, Hypoglycemia, Kidney Function Tests, Male, Middle Aged, Patient Discharge, Retrospective Studies, Risk Factors
Show Abstract · Added November 29, 2018
OBJECTIVE - Hypoglycemia is common in patients with diabetes. The risk of hypoglycemia after acute kidney injury (AKI) is not well defined. The purpose of this study was to compare the risk for postdischarge hypoglycemia among hospitalized patients with diabetes who do and do not experience AKI.
RESEARCH DESIGN AND METHODS - We performed a propensity-matched analysis of patients with diabetes, with and without AKI, using a retrospective national cohort of veterans hospitalized between 2004 and 2012. AKI was defined as a 0.3 mg/dL or 50% increase in serum creatinine from baseline to peak serum creatinine during hospitalization. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia or as an outpatient blood glucose <60 mg/dL. Time to incident hypoglycemia within 90 days postdischarge was examined using Cox proportional hazards models. Prespecified subgroup analyses by renal recovery, baseline chronic kidney disease, preadmission drug regimen, and HbA were performed.
RESULTS - We identified 65,151 propensity score-matched pairs with and without AKI. The incidence of hypoglycemia was 29.6 (95% CI 28.9-30.4) and 23.5 (95% CI 22.9-24.2) per 100 person-years for patients with and without AKI, respectively. After adjustment, AKI was associated with a 27% increased risk of hypoglycemia (hazard ratio [HR] 1.27 [95% CI 1.22-1.33]). For patients with full recovery, the HR was 1.18 (95% CI 1.12-1.25); for partial recovery, the HR was 1.30 (95% CI 1.23-1.37); and for no recovery, the HR was 1.48 (95% CI 1.36-1.60) compared with patients without AKI. Across all antidiabetes drug regimens, patients with AKI experienced hypoglycemia more frequently than patients without AKI, though the incidence of hypoglycemia was highest among insulin users, followed by glyburide and glipizide users, respectively.
CONCLUSIONS - AKI is a risk factor for hypoglycemia in the postdischarge period. Studies to identify risk-reduction strategies in this population are warranted.
© 2018 by the American Diabetes Association.
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Acute kidney injury is a risk factor for subsequent proteinuria.
Parr SK, Matheny ME, Abdel-Kader K, Greevy RA, Bian A, Fly J, Chen G, Speroff T, Hung AM, Ikizler TA, Siew ED
(2018) Kidney Int 93: 460-469
MeSH Terms: Acute Kidney Injury, Aged, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Comorbidity, Databases, Factual, Diabetes Mellitus, Diabetic Nephropathies, Disease Progression, Female, Glomerular Filtration Rate, Hospitalization, Hospitals, Veterans, Humans, Hypertension, Kidney, Male, Middle Aged, Prevalence, Prognosis, Proteinuria, Renal Insufficiency, Chronic, Retrospective Studies, Risk Factors, Severity of Illness Index, Time Factors, United States
Show Abstract · Added November 29, 2018
Acute kidney injury (AKI) is associated with subsequent chronic kidney disease (CKD), but the mechanism is unclear. To clarify this, we examined the association of AKI and new-onset or worsening proteinuria during the 12 months following hospitalization in a national retrospective cohort of United States Veterans hospitalized between 2004-2012. Patients with and without AKI were matched using baseline demographics, comorbidities, proteinuria, estimated glomerular filtration rate, blood pressure, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEI/ARB) use, and inpatient exposures linked to AKI. The distribution of proteinuria over one year post-discharge in the matched cohort was compared using inverse probability sampling weights. Subgroup analyses were based on diabetes, pre-admission ACEI/ARB use, and AKI severity. Among the 90,614 matched AKI and non-AKI pairs, the median estimated glomerular filtration rate was 62 mL/min/1.73m. The prevalence of diabetes and hypertension were 48% and 78%, respectively. The odds of having one plus or greater dipstick proteinuria was significantly higher during each month of follow-up in patients with AKI than in patients without AKI (odds ratio range 1.20-1.39). Odds were higher in patients with Stage II or III AKI (odds ratios 1.32-1.81) than in Stage I AKI (odds ratios 1.18-1.32), using non-AKI as the reference group. Results were consistent regardless of diabetes status or baseline ACEI/ARB use. Thus, AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. The type of proteinuria, physiology, and clinical significance warrant further study as a potentially modifiable risk factor in the pathway from AKI to CKD.
Published by Elsevier Inc.
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29 MeSH Terms
Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model.
Zhang MZ, Wang X, Yang H, Fogo AB, Murphy BJ, Kaltenbach R, Cheng P, Zinker B, Harris RC
(2017) J Am Soc Nephrol 28: 3300-3311
MeSH Terms: Animals, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Disease Models, Animal, Mice, Receptors, Lysophosphatidic Acid
Show Abstract · Added May 29, 2018
Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, -smooth muscle actin, connective tissue growth factor, collagen I, and TGF-; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, =4; at 20 weeks: 364±18 with vehicle, =7, and 536±12 with LPAR inhibition, =7; <0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.
Copyright © 2017 by the American Society of Nephrology.
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The novel adipokine/hepatokine fetuin B in severe human and murine diabetic kidney disease.
Kralisch S, Hoffmann A, Klöting N, Bachmann A, Kratzsch J, Blüher M, Zhang MZ, Harris RC, Stumvoll M, Fasshauer M, Ebert T
(2017) Diabetes Metab 43: 465-468
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Female, Fetuin-B, Humans, Male, Mice, Middle Aged, Renal Insufficiency, Chronic, Renal Replacement Therapy
Added June 2, 2017
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15 MeSH Terms