Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2+/−AkitaJ mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2+/−AkitaJ mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2+/−AkitaJ mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

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Changes of MicroRNA-377 in Diabetic Nephropathy

QJM ◽

10.1093/qjmed/hcaa052.052 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

H A Elshinnawy ◽

C R Kamel ◽

M H A Elkeleng

Keyword(s):

Diabetic Nephropathy ◽

Diabetic Patients ◽

Ckd Stage ◽

Significant Difference ◽

Group 3 ◽

Group 2 ◽

Stage Renal Disease ◽

End Stage ◽

Stage 1

Abstract Background as one of the most important long term complications of diabetes, Diabetic nephropathy is the major cause of end stage renal disease and high mortality. Purpose to identify the pattern of microRNA-377 changes specific for diabetic nephropathy in diabetic patients and in patients with chronic kidney disease of different etiology. Patients and Methods the study was conducted from 2016 to 2018, included 50 patients for analysis of MicroRNA-377 and its control gene U18 at El Demrdash Hospital Ain shams university and Quessena Hospital El Monfia. The miRNA-U18 was analyzed for normalization of correction ratio. Results the results of our research found that the highest median IQR of miR-377 was significantly present in DN stage 1&2 and the lowest median IQR was significantly present in CKD stage 1&2, and there was significant difference between group 1 (DN stage 1&2) versus group 2 (DN stage 3&4), group 3 (Diabetics without nephropathy) and all stages of CKD. Conclusion in diabetic nephropathy stage 1&2, serum miR-377 was highly significant increased more than diabetics without nephropathy, diabetic nephropathy stage 3&4 and all satges of CKD.

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Endoglin Promotes Myofibroblast Differentiation and Extracellular Matrix Production in Diabetic Nephropathy

International Journal of Molecular Sciences ◽

10.3390/ijms21207713 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7713

Author(s):

Tessa Gerrits ◽

Malu Zandbergen ◽

Ron Wolterbeek ◽

Jan A. Bruijn ◽

Hans J. Baelde ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Cell Function ◽

Interstitial Fibrosis ◽

Human Kidney ◽

Fibroblast Cell ◽

Diabetic Patients ◽

Endothelial Cell Function ◽

Intestinal Fibrosis ◽

Kidney Fibroblast ◽

Sirius Red

Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-β, is known primarily for regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and intestinal fibrosis. This study investigates whether endoglin contributes to the development of interstitial fibrosis in DN. Kidney autopsy material from 80 diabetic patients was stained for endoglin and Sirius Red and scored semi-quantitatively. Interstitial endoglin expression was increased in samples with DN and was correlated with Sirius Red staining (p < 0.001). Endoglin expression was also correlated with reduced eGFR (p = 0.001), increased creatinine (p < 0.01), increased systolic blood pressure (p < 0.05), hypertension (p < 0.05), and higher IFTA scores (p < 0.001). Biopsy samples from DN patients were also co-immunostained for endoglin together with CD31, CD68, vimentin, or α-SMA Endoglin co-localized with both the endothelial marker CD31 and the myofibroblast marker α-SMA. Finally, we used shRNA to knockdown endoglin expression in a human kidney fibroblast cell line. We found that TGF-β1 stimulation upregulated SERPINE1, CTGF, and ACTA2 mRNA and α-SMA protein, and that these effects were significantly reduced in fibroblasts after endoglin knockdown. Taken together, these data suggest that endoglin plays a role in the pathogenesis of interstitial fibrosis in DN.

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Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in Type I diabetic patients

Diabetologia ◽

10.1007/s001250051377 ◽

2000 ◽

Vol 43 (6) ◽

pp. 794-799 ◽

Cited By ~ 21

Author(s):

L. Tarnow ◽

T. Kjeld ◽

E. Knudsen ◽

A. Major-Pedersen ◽

H. -H. Parving

Keyword(s):

Diabetic Nephropathy ◽

Glycaemic Control ◽

Gene Polymorphisms ◽

Renin Angiotensin System ◽

Diabetic Patients ◽

Type I ◽

Angiotensin System ◽

Poor Glycaemic Control ◽

Renin Angiotensin

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Long-Term Outcomes of Japanese Type 2 Diabetic Patients With Biopsy-Proven Diabetic Nephropathy

Diabetes Care ◽

10.2337/dc13-0298 ◽

2013 ◽

Vol 36 (11) ◽

pp. 3655-3662 ◽

Cited By ~ 76

Author(s):

M. Shimizu ◽

K. Furuichi ◽

T. Toyama ◽

S. Kitajima ◽

A. Hara ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Diabetic Patients ◽

Long Term Outcomes ◽

Type 2 Diabetic Patients ◽

Type 2 Diabetic

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Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

BMC Nephrology ◽

10.1186/s12882-021-02510-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Miho Shimizu ◽

Kengo Furuichi ◽

Shinji Kitajima ◽

Tadashi Toyama ◽

Megumi Oshima ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Interstitial Fibrosis ◽

Long Term Outcomes ◽

Renal Interstitial Fibrosis ◽

Tubular Atrophy ◽

Tubulointerstitial Lesions ◽

The Impact

Abstract Background Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. Methods A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. Results At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. Conclusions Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

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Alteration of autophagy-related protein 5 (ATG5) levels and Atg5 gene expression in diabetes mellitus with and without complications

Diabetes and Vascular Disease Research ◽

10.1177/14791641211062050 ◽

2021 ◽

Vol 18 (6) ◽

pp. 147916412110620

Author(s):

Remah Yassin* ◽

Hagar Tadmor* ◽

Evgeny Farber ◽

Anas Igbariye ◽

Aida Armaly-Nakhoul ◽

...

Keyword(s):

Diabetes Mellitus ◽

Diabetic Retinopathy ◽

Diabetic Nephropathy ◽

Western Blot ◽

Mononuclear Cells ◽

Immunohistochemical Analysis ◽

Diabetic Patients ◽

Healthy Controls ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

Background Autophagy is a catabolic mechanism that involves lysosomal-dependent degradation of unnecessary intracellular components and responsible for normal cellular homeostasis. Autophagy pathway and its key participant ATG5/LC3 are associated with several pathologies such as diabetes mellitus and its complications. Methods Levels and expression of autophagy key components ATG5 and LC3B were analyzed in both human model and murine tissues. One hundred and twenty human subjects were divided into four groups: Healthy (control), diabetes mellitus without complications, diabetic nephropathy, and diabetic retinopathy. Additionally, we used kidneys from WT healthy and diabetic nephropathy mice. Lysate derived from human peripheral blood mononuclear cells and murine renal cortex lysates were subjected to western blot and immunohistochemical analysis. Results Western blot and immunohistochemical analysis demonstrate that ATG5 protein levels were significantly decreased in diabetes mellitus, diabetic nephropathy (DN), and diabetic retinopathy patients versus healthy controls and in DN mice compared to healthy mice (0.65 ± 0.04; 1.15 ± 0.13 A.U. units, respectively). Quantification of staining area (%) of ATG5 mice tissue expression also decreased in DN versus healthy mice (4.42 ± 1.08%; 10.87 ± 1.01%, respectively). LC3B levels and expression Significant reduction in peripheral blood mononuclear cells in diabetic patients (with or without complications) vs. healthy controls. Renal LC3B levels were lower in DN versus healthy mice (0.36 ± 0.03; 0.68 ± 0.07 A.U. units). Renal LC3B staining quantification revealed significant reduction in DN versus healthy mice (1.7 ± 0.23%; 8.56 ± 1.7%). Conclusion We conclude that ATG5, as well as LC3B, are down regulated in diabetic patients with or without complications. This diminution contributes to deficiencies in the autophagy process.

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P0984SGLT2 INHIBITION PREVENTS RENAL FIBROSIS IN CYCLOSPORINE NEPHROPATHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0984 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Giovanna Castoldi ◽

Raffaella Carletti ◽

Silvia Ippolito ◽

Massimiliano Colzani ◽

Francesca Barzaghi ◽

...

Keyword(s):

Blood Pressure ◽

Diabetic Nephropathy ◽

Tyrosine Hydroxylase ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Control Group ◽

Diabetic Patients ◽

Protective Effects ◽

Type 2 Diabetic Patients ◽

Inflammatory Infiltrates

Abstract Background and Aims Sodium glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, showed nephroprotection in type 2 diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is unclear whether the nephroprotective effects are present also in non-diabetic nephropathy. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, in cyclosporine nephropathy in the absence of diabetes. Method Ten days before the beginning and then during the entire experimental periods, low-salt diet (Teklad 7034) was administered to Sprague Dawley rats. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection; n=6) and CsA plus empagliflozin (Empa, 10 mg/kg /day, per os; n=6) were administered for 4 weeks. Control group was treated with placebo (n=6). Blood pressure was measured by plethysmographic method at the beginning and at the end of the experimental period. At the end of the protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and tyrosine hydroxylase expression, used as marker of symphatetic nerve activity. Results The rats treated with CsA showed a significant increase (p <0.01) in blood pressure, which was slightly reduced by administration of empagliflozin. CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p <0.05), renal inflammatory infiltrates (p <0.05) and tyrosine hydroxylase expression (p <0.01) as compared to the control rats. Treatment with empagliflozin reduced glomerular and tubulo-interstitial fibrosis (p <0.05), inflammatory cell infiltration (p <0.01) and tyrosine hydroxylase expression (p <0.01), as compared to CsA-treated rats. Conclusion Empagliflozin administration showed protective effects on cyclosporine nephropathy, decreasing renal fibrosis, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that the nephroprotective role of empagliflozin could not be restricted only to diabetic nephropathy.

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