Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes

Carvalho, José Antônio Mainardi de; Tatsch, Etiane; Hausen, Bruna S.; Bollick, Yãnaí S.; Moretto, Maria Beatriz; Duarte, Thiago; Duarte, Marta M.M.F.; Londero, Sílvia W.K.; Premaor, Melissa Orlandin; Comim, Fábio Vasconcellos; Delanghe, Joris; Moresco, Rafael Noal

doi:10.1016/j.clinbiochem.2015.10.016

Cited by 88 publications

(75 citation statements)

References 34 publications

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“…Meanwhile, urinary KIM-1 and NGAL are elevated in type 2 diabetic rats with early signs of DN [28, 29], even not STZ-induced [28]. These findings are congruent with the results of clinical studies indicating that urinary KIM-1 and NGAL are sensitive biomarkers of early, preclinical stage of DN in patients with DM2 [30–32]. …”

Section: Introductionsupporting

confidence: 56%

Uninephrectomized High-Fat-Fed Nicotinamide-Streptozotocin-Induced Diabetic Rats: A Model for the Investigation of Diabetic Nephropathy in Type 2 Diabetes

Bayrasheva

Бабенко

Добронравов

et al. 2016

Journal of Diabetes Research

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Type 2 diabetes (DM2) could be reproduced in rats with alimentary obesity by using low doses of streptozotocin (LD-STZ) as well as STZ in high doses with preliminary nicotinamide (NA) administration. However, STZ could induce tubulotoxicity. Aim. To develop rat model of DN in NA-STZ-induced DM2 and compare it with LD-STZ-model in order to choose the most relevant approach for reproducing renal glomerular and tubular morphofunctional diabetic changes. Starting at 3 weeks after uninephrectomy, adult male Wistar rats were fed five-week high-fat diet and then received intraperitoneally either LD-STZ (40 mg/kg) or NA (230 mg/kg) followed by STZ (65 mg/kg). Control uninephrectomized vehicle-injected rats received normal chow. At weeks 10, 20, and 30 (the end of the study), metabolic parameters, creatinine clearance, albuminuria, and urinary tubular injury markers (NGAL, KIM-1) were evaluated as well as renal ultrastructural and light microscopic changes at weeks 20 and 30. NA-STZ-group showed higher reproducibility and stability of metabolic parameters. By week 10, in NA-STZ-group NGAL level was significantly lower compared to LD-STZ-group. By week 30, diabetic groups showed early features of DN. However, morphofunctional changes in NA-STZ-group appeared to be more pronounced than those in STZ-group despite lower levels of KIM-1 and NGAL. We proposed a new rat model of DM2 with DN characterized by stable metabolic disorders, typical renal lesions, and lower levels of tubular injury markers as compared to LD-STZ-induced diabetes.

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Section: Introductionsupporting

confidence: 56%

Uninephrectomized High-Fat-Fed Nicotinamide-Streptozotocin-Induced Diabetic Rats: A Model for the Investigation of Diabetic Nephropathy in Type 2 Diabetes

Bayrasheva

Бабенко

Добронравов

et al. 2016

Journal of Diabetes Research

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“…[35], [36] Tubular injury contributes to primary renal injury, rather than secondary injury, in the pathogenesis of DKD, which is reflected by the fact that tubular damage markers appear before microalbuminuria. [37], [38], [39], [40] The mechanisms underlying these phenomena are not fully clear, but others and our previous studies have demonstrated that dysfunctional mitochondria play a crucial role in this process. [6], [7], [8], [9] Increasing evidence indicates that mitochondrial ROS overproduction, decreases in ATP activity and increases in mitochondrial fragmentation may be related to tubular cell damage and apoptosis in DKD.…”

Section: Discussionmentioning

confidence: 99%

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

et al. 2017

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Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

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“…Wu et al reported that serum NGAL level may serve as a new biomarker for the diagnosis of diabetic kidney disease (DKD) in T2DM [25]. De Carvalho et al showed that NGAL was enhanced in T2DM patients with normal or mildly increased albuminuria, which indicated that tubular and glomerular injuries may be occurring even at the earliest stage of DKD [26]. Nielsen et al found that urinary NGAL was elevated in type1diabetic (T1DM) patients with or without albuminuria, demonstrating tubular damage at an early stage [27].…”

Section: Discussionmentioning

confidence: 99%

Urinary RBP and NGAL Levels are Associated with Nephropathy in Patients with Type 2 Diabetes

Shao

et al. 2017

Cell Physiol Biochem

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Background/Aims: The diagnosis of type 2 diabetic nephropathy (T2DN) patients is important to prevent the long-term damaging effects of kidney loss in patients with diabetes and is decisive for patient outcomes. The aim of this study was to explore urine retinol binding protein (RBP) and neutrophil gelatinase-associated lipocalin (NGAL) in T2DN patients with and without albuminuria. Methods: A total of 293 T2DN patients were divided into three groups according to their urine albumin/urine creatinine ratio (UACR): normoalbuminuria group (UACR<30 mg/g, n=100), microalbuminuria group (UACR 30–300 mg/g, n=100) and macroalbuminuria group (UACR>300 mg/g, n=93); 50 non-diabetic subjects were recruited as the control group. The levels of urine RBP, NGAL, TNF-α and IL-18 in T2DN patients and non-diabetic subjects were measured using ELISA assays. Results: We first analyzed the clinical characteristics of the control and T2DN groups and found that urine NGAL, RBP, TNF-α and IL-18 levels were significantly increased and significantly correlated with the degree of albuminuria. In addition, univariate linear regression analysis showed that urine RBP was associated with UACR, BMI, Scr, BUN, TG, disease duration, SBP, NGAL, TNF-α and IL-18 levels, and urine NGAL was positively correlated with UACR, Scr, BUN, RBP, TNF-α and IL-18 levels. Conclusion: The results indicate that urine levels of NGAL and RBP may be independently associated with albuminuria in T2DN and may serve as novel biomarkers for the identification of T2DN.

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Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes

Cited by 88 publications

References 34 publications

Uninephrectomized High-Fat-Fed Nicotinamide-Streptozotocin-Induced Diabetic Rats: A Model for the Investigation of Diabetic Nephropathy in Type 2 Diabetes

Uninephrectomized High-Fat-Fed Nicotinamide-Streptozotocin-Induced Diabetic Rats: A Model for the Investigation of Diabetic Nephropathy in Type 2 Diabetes

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

Urinary RBP and NGAL Levels are Associated with Nephropathy in Patients with Type 2 Diabetes

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