Evidence of Early Diabetic Nephropathy in Pediatric Type 1 Diabetes

Mamilly, Leena; Mastrandrea, Lucy D.; Vasquez, Claudia Mosquera; Klamer, Brett; Kallash, Mahmoud; Aldughiem, Ahmad

doi:10.3389/fendo.2021.669954

Cited by 14 publications

(23 citation statements)

References 36 publications

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“…DN is a nearly ubiquitous end organ-complication of diabetes, reflective of the fact that chronic hyperglycemia is a major cause of podocyte injury. This injury results in increased GFB permeability evidenced by the development of albuminuria, followed by the progression to glomerulosclerosis 10,[49][50][51] . The ability to identify the earliest pathophysiological events of DN and intervene in these before the development of diabetic kidney injury holds the greatest promise for improving disease outcome.…”

Section: Discussionmentioning

confidence: 99%

Dynein-mediated trafficking and degradation of nephrin in diabetic podocytopathy

Sun

Weidner

Allamargot

et al. 2022

Preprint

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Diabetic nephropathy (DN) is characterized by increased endocytosis and degradation of nephrin, a protein that comprises the molecular sieve of the glomerular filtration barrier, but the key trafficking mechanism that connects the initial endocytic events and the homeostasis of nephrin is unknown. Our work implicates cytoplasmic dynein, a transport complex that is upregulated in DN, plays a critical role in triaging the endocytosed nephrin between recycling and proteolytic pathways. Using Nephroseq platform, our transcription analysis in public DN databases revealed dynein overexpression in human DN and diabetic mouse kidney, correlated with the severity of hyperglycemia and nephropathy. The increased expression of dynein subunits was confirmed in high glucose-treated podocytes and in glomeruli isolated from streptozotocin (STZ)-induced diabetic mice. Using live cell imaging, we illustrated that dynein-mediated post-endocytic sorting of nephrin was upregulated, resulting in accelerated nephrin degradation and disrupted nephrin recycling. In diabetic podocytopathy, Dynll1 is one of the most upregulated dynein components that was recruited to endocytosed nephrin. This was corroborated by observing enhanced Dynll1-nephrin colocalization in podocytes of diabetic patients, as well as dynein-mediated trafficking and degradation of nephrin in STZ-induced diabetic mice. Knockdown of Dynll1 attenuated lysosomal degradation of nephrin and promoted its recycling, suggesting the essential role of Dynll1 in dynein-mediated mistrafficking. Defining the role of dynein-mediated mistrafficking of nephrin in diabetes will not only fill the knowledge gap about the early events of DN, but also inspire novel therapeutics that target a broad spectrum of molecular events involved in the dynein-mediated trafficking.

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Section: Discussionmentioning

confidence: 99%

Dynein-mediated trafficking and degradation of nephrin in diabetic podocytopathy

Sun

Weidner

Allamargot

et al. 2022

Preprint

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“…Urinary NGAL level increases before the onset of microalbuminuria in the very early phase of the kidney disease[ 48 ]. Alongside urinary biomarkers of tubular health (NGAL), the oxidative stress biomarker (pentosidine) may be used in the early detection of diabetic nephropathy before the microalbuminuric phase, as they correlate with albumin excretion and loss of nocturnal dipping of SBP and mean arterial BP[ 49 ].…”

Section: Diagnosismentioning

confidence: 99%

“…Mamilly et al [ 49 ] found an increased urinary NGAL/creatinine (a marker of tubular injury) and pentosidine/creatinine (a marker of oxidative stress) in subjects with T1DM compared to controls even in the absence of microalbuminuria[ 49 ]. The same study reported a high incidence of abnormal BP dipping, which is important because dipping abnormalities may serve as a predictor for vascular complications, especially kidney injury in diabetic individuals[ 49 ]. The same study proved that urine NGAL correlates with loss of nocturnal dipping of SBP[ 49 ].…”

Section: Diagnosismentioning

confidence: 99%

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Diabetic kidney disease in pediatric patients: A current review

Muntean¹,

Stârcea²,

Banescu³

2022

WJD

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In the last decades, a significant increase in the incidence of diabetic kidney disease (DKD) was observed concomitant with rising diabetes mellitus (DM) incidence. Kidney disease associated with DM in children and adolescents is represented by persistent albuminuria, arterial hypertension, progressive decline in estimated glomerular filtration rate to end-stage renal disease and increased cardiovascular and all-cause morbidity and mortality of these conditions. In medical practice, the common and still the “gold standard” marker for prediction and detection of diabetic kidney involvement in pediatric diabetes is represented by microalbuminuria screening even if it has low specificity to detect early stages of DKD. There are some known limitations in albuminuria value as a predictor biomarker for DKD, as not all diabetic children with microalbuminuria or macroalbuminuria will develop end-stage renal disease. As tubular damage occurs before the glomerular injury, tubular biomarkers are superior to the glomerular ones. Therefore, they may serve for early detection of DKD in both type 1 DM and type 2 DM. Conventional and new biomarkers to identify diabetic children and adolescents at risk of renal complications at an early stage as well as renoprotective strategies are necessary to delay the progression of kidney disease to end-stage kidney disease. New biomarkers and therapeutic strategies are discussed as timely diagnosis and therapy are critical in the pediatric diabetic population.

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“…Maintaining strict glycemic control is key to early prevention of the development of the complications of this disease [ 1 ]. Diabetic nephropathy (DN) is one of the major diabetes-associated adverse outcomes, characterized by albuminuria, hypertension, and the deterioration of renal function [ 2 ]. Numerous biomarkers have been introduced to assess tubulointerstitial damage.…”

Section: Introductionmentioning

confidence: 99%

High Glycated Hemoglobin Instead of High Body Mass Index Might Increase the Urine N-Acetyl-β-D-glucosaminidase Con-Centration in Children and Adolescents with Diabetes Mellitus

Suh

Kim

et al. 2022

Life

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Children with diabetes, and particularly those with obesity, have poor glycemic control. They are thus at higher risk of early microvascular complications. Renal tubulointerstitial markers are integral to evaluating diabetic nephropathy. Various biomarkers have been proposed, but their role in the obese pediatric population is uncertain. We investigated renal injury markers in children with diabetes, according to obesity, and determined their role as early predictors of diabetic nephropathy. Fifty-three children and adolescents, diagnosed with either type 1 or 2 diabetes mellitus, and 43 control children, aged 7–18 years, were included. Clinical and laboratory characteristics, including six renal injury markers, were compared among subjects according to body mass index and presence of diabetes mellitus. Urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and N-acetyl-β-D-glucosaminidase (NAG) showed significant difference between controls and diabetic children, whereas urine NAG was the only biomarker that was significantly lower either in non-obese or obese controls as compared to diabetic children. Urine NGAL, KIM-1, and NAG showed significant correlations with both HbA1c and urine ACR, whereas only urine NAG was significantly correlated with HbA1c even when groups were subdivided based on the presence of either obesity or diabetes. After adjusting for age, sex, body mass index, duration of known diabetes, and urine albumin-to-creatinine ratio, HbA1c remained a significant risk factor for elevated urine NAG. Urine NAG could be a useful indicator of tubulointerstitial damage in children with diabetes in the pre-albuminuric state. Tighter glycemic control appears to be crucial for avoiding early progression to diabetic nephropathy.

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Evidence of Early Diabetic Nephropathy in Pediatric Type 1 Diabetes

Cited by 14 publications

References 36 publications

Dynein-mediated trafficking and degradation of nephrin in diabetic podocytopathy

Dynein-mediated trafficking and degradation of nephrin in diabetic podocytopathy

Diabetic kidney disease in pediatric patients: A current review

High Glycated Hemoglobin Instead of High Body Mass Index Might Increase the Urine N-Acetyl-β-D-glucosaminidase Con-Centration in Children and Adolescents with Diabetes Mellitus

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