Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: From current human evidence to future possibilities

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Abstract

Although hyperglycemia, high blood pressure and aging increase the risk of developing kidney complications, some diabetes patients exposed to these risk factors do not develop kidney disease, suggesting the presence of endogenous protective factors. There is a growing need to understand these factors determining protection of the kidney in order to improve the design of preventive strategies and to enhance the processes responsible for renoprotection. The aim of this review was to present the existing molecular and epidemiological data on factors showing protective effects in diabetic kidney disease, and to summarize the evidence regarding their potential in the area of future clinical diagnostics, therapeutics and early preventive strategies. These include transcriptomic and proteomic studies regarding the anti‐inflammatory, anti‐fibrotic and regenerative factors that were associated with slower progression of renal function loss. Another focus is the new evidence regarding the evaluation of alterations in the regulatory epigenome and its involvement in the risk of diabetic kidney disease. Further effort is required to validate and extend these findings, and to define their potential for clinical implementation in the future.

Abstract

Recent studies have characterized a number of novel risk and protective factors contributing to the variability in the interindividual risk of initiation and progression of diabetic kidney disease. Both these facets of diabetic nephropathy pathophysiology will inform the management of diabetes patients, and will be important to attenuate the incidence of end‐stage renal disease attributed to diabetic kidney disease. The aim of this review was to present the existing molecular and epidemiological data on factors showing protective effects in diabetic kidney disease, and to summarize the evidence regarding their potential in the area of future clinical diagnostics, therapeutics and early preventive strategies.

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Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy.

Juan F. Navarro-González, Carmen Mora-Fernández, Mercedes Muros de Fuentes … (2011)

Many lines of evidence, ranging from in vitro experiments and pathological examinations to epidemiological studies, show that inflammation is a cardinal pathogenetic mechanism in diabetic nephropathy. Thus, modulation of inflammatory processes in the setting of diabetes mellitus is a matter of great interest for researchers today. The relationships between inflammation and the development and progression of diabetic nephropathy involve complex molecular networks and processes. This Review, therefore, focuses on key proinflammatory molecules and pathways implicated in the development and progression of diabetic nephropathy: the chemokines CCL2, CX3CL1 and CCL5 (also known as MCP-1, fractalkine and RANTES, respectively); the adhesion molecules intercellular adhesion molecule 1, vascular cell adhesion protein 1, endothelial cell-selective adhesion molecule, E-selectin and α-actinin 4; the transcription factor nuclear factor κB; and the inflammatory cytokines IL-1, IL-6, IL-18 and tumor necrosis factor. Advances in the understanding of the roles that these inflammatory pathways have in the context of diabetic nephropathy will facilitate the discovery of new therapeutic targets. In the next few years, promising new therapeutic strategies based on anti-inflammatory effects could be successfully translated into clinical treatments for diabetic complications, including diabetic nephropathy.

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Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease.

Merlin Thomas, Mark E. Cooper, Paul Zimmet (2016)

Chronic kidney disease (CKD) is a common comorbidity in patients with type 2 diabetes mellitus (T2DM) and both conditions are increasing in prevalence. CKD is estimated to affect ∼50% patients with T2DM globally, and its presence and severity markedly influences disease prognosis. CKD is more common in certain patient populations, including the elderly, those with youth-onset diabetes mellitus, those who are obese, certain ethnic groups, and disadvantaged populations. These same settings have also seen the greatest increase in the prevalence of T2DM, as exemplified by the increasing prevalence of T2DM in low-to- middle income countries. Patients from low-to-middle income countries are often the least able to deal with the burden of T2DM and CKD and the health-care facilities of these countries least able to deal with the demand for equitable access to renal replacement therapies. The increasing prevalence of younger individuals with T2DM, in whom an accelerated course of complications can be observed, further adds to the global burden of CKD. Paradoxically, improvements in cardiovascular survival in patients with T2DM have contributed to patients surviving longer, allowing sufficient time to develop renal impairment. This Review explores how the changing epidemiology of T2DM has influenced the prevalence and incidence of associated CKD across different populations and clinical settings.

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MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors.

Mitsuo Kato, Jane Zhang, Mei Wang … (2007)

Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-alpha 1 and -2 (Col1a1 and -2). Transforming growth factor beta1 (TGF-beta), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-beta increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, deltaEF1. TGF-beta treatment or short hairpin RNAs targeting deltaEF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-beta also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to deltaEF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), a key miR highly expressed in the kidney. miR-192 levels also were increased by TGF-beta in MMC. TGF-beta treatment or transfection with miR-192 decreased endogenous SIP1 expression as well as reporter activity of a SIP1 3' UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitor enhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192 synergized with deltaEF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the in vivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative to corresponding nondiabetic controls, in parallel with increased TGF-beta and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-beta-induced Col1a2 expression by down-regulating E-box repressors.

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Author and article information

Contributors

Natalia Nowak:

ORCID: https://orcid.org/0000-0002-1019-1395

nzuznowak@gmail.com , natalia.nowak@umb.edu.pl

Journal

Journal ID (nlm-ta): J Diabetes Investig

Journal ID (iso-abbrev): J Diabetes Investig

Journal ID (doi): 10.1111/(ISSN)2040-1124

Journal ID (publisher-id): JDI

Title: Journal of Diabetes Investigation

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 2040-1116

ISSN (Electronic): 2040-1124

Publication date (Electronic): 06 May 2020

Publication date (Print): September 2020

Volume: 11

Issue: 5 ( doiID: 10.1111/jdi.v11.5 )

Pages: 1085-1096

Affiliations

[ ¹ ] Faculty of Medicine Center for Bioinformatics and Data Analysis Medical University of Bialystok Bialystok Poland

Author notes

[*] [* ] Correspondence

Natalia Nowak

Tel.: +48-51-451-02-74

Fax: +48-85-748-54-16

E‐mail addresses: nzuznowak@ 123456gmail.com ; natalia.nowak@ 123456umb.edu.pl

Author information

Natalia Nowak https://orcid.org/0000-0002-1019-1395

Article

Publisher ID: JDI13257

DOI: 10.1111/jdi.13257

PMC ID: 7477513

PubMed ID: 32196975

SO-VID: b32ff362-999b-4a5a-af6f-9b0c3672708b

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 28 November 2019

Date revision received : 03 March 2020

Date accepted : 17 March 2020

Page count

Figures: 2, Tables: 2, Pages: 12, Words: 8734

Funding

Funded by: Uniwersytet Medyczny w Bialymstoku , open-funder-registry 10.13039/501100005297;

Award ID: SUB/1/DN/20/002/4407

Custom metadata

source-schema-version-number 2.0

cover-date September 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.9 mode:remove_FC converted:08.09.2020

Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: From current human evidence to future possibilities

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Biomarkers for Inflammatory Lung Disease

Most cited references 76

Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy.

Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease.

MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors.

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