High expression of neutrophil gelatinase-associated lipocalin (NGAL) in the kidney proximal tubules of diabetic rats

Li, Fenghua; Yang, Huayu; Chen, Haiping; Zhang, Mi; Ma, Qing

doi:10.1016/j.advms.2015.01.001

Cited by 28 publications

(22 citation statements)

References 32 publications

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“…Although the results from the present study tend to imply increased NGAL and KIM1 in diabetic rats chronically treated with TEMPOL, it is unclear how this translates to long-term outcome given the lack of solid literature support for a relationship between these biomarkers and progression of diabetic nephropathy. Indeed, previous reports have demonstrated a time-dependent regulation of these genes (9,18). The efficiency of the antioxidant treatment is most likely time-dependent, i.e.…”

Section: Discussionmentioning

confidence: 97%

Antioxidant treatment attenuates lactate production in diabetic nephropathy

Laustsen

Nielsen

Nørlinger

et al. 2017

American Journal of Physiology-Renal Physiology

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The early progression of diabetic nephropathy is notoriously difficult to detect and quantify prior to the occurrence of substantial histological damage. Recently, hyperpolarized [1-13 C] pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging.Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 weeks after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13 C/ 1 H-volume rat coil. The rats received intravenous hyperpolarized [1-13 C] pyruvate and were imaged using a slice-selective 13 C-IDEAL spiral sequence.Untreated diabetic rats showed increased renal lactate production compared to that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on 13 C-alanine levels,indicating an intact glucose-alanine cycle, or 13 C-bicarbonate, indicating normal flux through the Krebs cycle.In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress for renal metabolic alterations occurring in early diabetes.4

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Section: Discussionmentioning

confidence: 97%

Antioxidant treatment attenuates lactate production in diabetic nephropathy

Laustsen

Nielsen

Nørlinger

et al. 2017

American Journal of Physiology-Renal Physiology

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“…Previous investigations have demonstrated that NGAL is highly expressed in the kidney proximal tubules of diabetic rats [13, 26] and uNGAL is markedly elevated in microalbuminuric patients with T1DM [22, 34] or T2DM [35, 36], uNGAL is positively correlated with proteinuria, and can reflect the severity of diabetic nephropathy [36, 37]. Urinary CysC has also been suggested as an indicator of tubular dysfunction for the early diagnosis of DKD [21, 38, 39].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it can be assumed that the level of each marker in urine may change significantly, given that tubular impairment plays an important role in the pathogenesis underlying DKD [20, 21]. Previous studies have demonstrated that markedly increased levels of biomarkers are positively correlated with albuminuria and reflect the severity of renal damage in diabetic cohorts [22–24] or animal models [13, 25, 26]. Renal impairment that is mainly caused by hyperglycemia, however, has a different and more complicated pathogenesis compared with renal ischemia, hypoxic damage, or toxic injury, and thus the feasibility and efficacy of these biomarkers warrants further confirmation in clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Performance of urinary neutrophil gelatinase-associated lipocalin, clusterin, and cystatin C in predicting diabetic kidney disease and diabetic microalbuminuria: a consecutive cohort study

Zeng

Lyu

et al. 2017

BMC Nephrol

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BackgroundTubular biomarkers have been regarded as emerging and promising markers for early diagnosis of diabetic kidney disease (DKD). The study was to determine the diagnostic capabilities of tubular biomarkers (urinary neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and cystatin C) for DKD and diabetic microalbuminuria, and whether or not the tubular biomarkers appear earlier than microalbuminuria.MethodsIn this consecutive cohort study, 146 type 2 diabetes mellitus (T2DM) patients with a disease duration of ≥6 years were enrolled. Thirty age- and gender-matched subjects without any systemic diseases were recruited as the control group. Urinary samples collected before treatment were tested for NGAL, clusterin, and cystatin C.ResultsThe levels of biomarkers were higher in patients with DKD (p < 0.001); and positively correlated with the urinary albumin creatinine ratio (UACR; p < 0.001). With respect to the diagnosis of DKD, the areas under the receiver operating characteristic curve (AUCs) for urinary NGAL, clusterin, and cystatin C were 0.816 (95% confidence interval [CI], 0.741–0.891), 0.775 (95% CI: 0.694–0.857), and 0.803 (95% CI: 0.722–0.884), respectively. The levels of urinary NGAL and cystatin C in the normoalbuminuria group (UACR <30 mg /g•Cr) were elevated compared with the control group, unlike urinary clusterin. There was no statistical difference in the levels of the three biomarkers between groups with different levels of haemoglobin A1C (HbA1c). The diagnostic AUCs for urinary NGAL, clusterin, and cystatin C in patients with diabetic microalbuminuria were 0.841 (95% CI: 0.775–0.907), 0.783(95% CI: 0.710–0.856), and 0.805 (95% CI: 0.733–0.877), respectively.ConclusionsUrinary NGAL, clusterin, and cystatin C may be promising biomarkers for diagnosing DKD and diabetic microalbuminuria. It is possible that urinary NGAL and cystatin C increase before the onset of microalbuminuria in T2DM patients.

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“…The neutrophil gelatinase-associated lipocalin protein (NGAL) has been identified as a novel MR target in the cardiovascular system [ 124 ]. The neutrophil gelatinase-associated lipocalin protein is a 25-kDa glycoprotein of the lipocalin superfamily [ 125 ] expressed by several cell types, including renal cells [ 126 ], ECs and SMCs [ 127 , 128 ], cardiomyocytes [ 124 ] and some immune cells subpopulations, such as neutrophils, macrophages, and DCs [ 128 , 129 , 130 , 131 ]. This protein is a marker of renal injury [ 132 ].…”

Section: Mineralocorticoid Receptor Downstream Molecules: Novel Bimentioning

confidence: 99%

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease

et al. 2018

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The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome.

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High expression of neutrophil gelatinase-associated lipocalin (NGAL) in the kidney proximal tubules of diabetic rats

Cited by 28 publications

References 32 publications

Antioxidant treatment attenuates lactate production in diabetic nephropathy

Antioxidant treatment attenuates lactate production in diabetic nephropathy

Performance of urinary neutrophil gelatinase-associated lipocalin, clusterin, and cystatin C in predicting diabetic kidney disease and diabetic microalbuminuria: a consecutive cohort study

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease

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