Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model

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Abstract

Uncontrolled activation of transforming growth factor beta (TGF-β) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-β family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-β family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members.

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Pathologic classification of diabetic nephropathy.

Thijs W Cohen Tervaert, Antien Mooyaart, Kerstin Amann … (2010)

Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.

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Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling.

Hariom Yadav, Celia Quijano, Anil Kamaraju … (2011)

Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes. Copyright © 2011 Elsevier Inc. All rights reserved.

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Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.

H. Chen, O Charlat, L A Tartaglia … (1996)

OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.

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Author and article information

Journal

Journal ID (nlm-ta): Ren Fail

Journal ID (iso-abbrev): Ren Fail

Journal ID (publisher-id): IRNF

Journal ID (publisher-id): irnf20

Title: Renal Failure

Publisher: Taylor & Francis

ISSN (Print): 0886-022X

ISSN (Electronic): 1525-6049

Publication date Collection: 2017

Publication date (Electronic): 14 August 2017

Volume: 39

Issue: 1

Pages: 629-642

Affiliations

[a ]Department of Diabetes Complications Research, Novo Nordisk A/S , Måløv, Denmark;

[b ]Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus, Denmark;

[c ]Department of Incretin & Obesity Pharmacology, Novo Nordisk A/S , Måløv, Denmark;

[d ]Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center , Leiden, The Netherlands;

[e ]Department of Pathology, Leiden University Medical Center , Leiden, The Netherlands

Author notes

CONTACT Morten Fog-Tonnesen mtnt@ 123456novonordisk.com Novo Nordisk A/S, Liver Disease Pharmacology , Novo Nordisk Park, DK-2760Maaloev, Denmark

Article

Publisher ID: 1361837

DOI: 10.1080/0886022X.2017.1361837

PMC ID: 6446227

PubMed ID: 28805484

SO-VID: 25b581ef-c3df-4822-9fc1-5ecb8dc5a961

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 03 February 2017

Date revision received : 23 May 2017

Date accepted : 25 July 2017

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Pages: 14, Words: 7485

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Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model

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Karger: Nephrology

Most cited references 55

Pathologic classification of diabetic nephropathy.

Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling.

Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.

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