Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets

Sharma, Dilip Kumar; Bhattacharya, Pallab; Kalia, Kiran; Tiwari, Vinod

doi:10.1016/j.diabres.2017.04.010

Cited by 116 publications

(79 citation statements)

References 126 publications

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“…Renal tubulointerstitial fibrosis is a crucial procession of DN toward ESRD [30]. The macrophage is well recognized for the pathogenic role in kidney inflammation and EMT, which contributes to the renal fibrosis progression [15-17].…”

Section: Discussionmentioning

confidence: 99%

High-Mobility Group Nucleosome-Binding Protein 1 Mediates Renal Fibrosis Correlating with Macrophages Accumulation and Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy Mice Model

Dong

et al. 2019

Kidney Blood Press Res

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Background/Aim: Renal fibrosis is essential for the progression of diabetic nephropathy (DN). Macrophages accumulate in diabetic kidneys and are involved in epithelial-to-mesenchymal transition (EMT), a vital mechanism leading to renal fibrosis. Recently, high-mobility group nucleosome-binding protein 1(HMGN1) was documented in promoting the recruitment and activation of antigen-presenting cells. In this study, we first reported its roles in renal fibrosis and the underlying mechanism associated with macrophage filtration and EMT. Methods: Twenty C57BL/6J mice were administered streptozotocin (STZ) to induce diabetes for 6 weeks and then divided into 4 groups: normal control group; DN group; benazepril-treated group, and insulin-treated group. Blood glucose, creatinine, and albumin in urine, hematoxylin and eosin, and Sirius red staining of kidney tissues were used to assess the renal pathology. ELISA, immunochemistry, and in situ hybridization were performed to determine the expression of HMGN1, CD68, F4/80, α-smooth muscle actin, and E-cadherin. Results: The renal expression levels of HMGN1, macrophage markers, and EMT makers were increased in DN group, and insulin treatment could reduce the overexpression of these indicators with a better effect than benazepril treatment. Both treatments could not obviously ameliorate urine albumin-to-creatinine ratio, collagen expression, and renal histological changes in STZ-induced diabetic mice. Correlation analysis indicated that there was a relationship among HMGN1, macrophage markers, EMT markers, and collagen expression in DN mice. Conclusion: HMGN1 may promote macrophages accumulation and EMT, suggesting a potential therapeutic target for preventing renal fibrosis development in DN.

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Section: Discussionmentioning

confidence: 99%

High-Mobility Group Nucleosome-Binding Protein 1 Mediates Renal Fibrosis Correlating with Macrophages Accumulation and Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy Mice Model

Dong

et al. 2019

Kidney Blood Press Res

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“…Diabetic nephropathy (DN), as one of the most common microvascular complication among patients who suffer from diabetes, is revealed as the major reason for renal failure as compared with other kidney diseases [21]. As the most common attribution for the chronic kidney disease [22], it is a well-known risk factor for the cardiovascular events and its mortality and often a pivotal complication of diabetes [23,24].…”

Section: Dn and Podocytementioning

confidence: 99%

The Effect of Endoplasmic Reticulum Stress on Podocyte Apoptosis in Diabetic Nephropathy

Ren¹

2020

Molecular Biology &Amp; Nanomedicine

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Diabetic nephropathy (DN) has already become the leading reason for the end-stage renal disease throughout the world. As current therapeutic strategy for progression of DN remained only moderately successful, the underlying mechanisms remain less understood. Endoplasmic reticulum (ER), mitochondria, and death receptor could activate apoptotic pathways, such as caspase-independent pathways. Accumulating evidence indicated that ER stress played a major role in the development and progression of DN. And the aberrant activation of ER stress induced both the inflammation and cellular apoptosis, and modulate the signaling of protective processes including the autophagy. In addition, a growing number of evidences suggested that glomerular podocyte was the key player in DN, and yet the mechanism how ER signaling affected the podocyte apoptosis remained to be well-understood. Because podocytes are terminally differentiated epithelial cells in lack of the capability to proliferate, thus the loss of podocytes is a significant biomarker of progressive kidney diseases, including DN. Hence, the podocyte apoptosis is to be of great significance for the DN treatment. In this review, we summarized relevant apoptotic pathways involved in excessive ER stress-induced apoptosis.

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“…Pathogenesis of DN is a complex and multifactorial process that appears to be a combination of inflammation, oxidative stress, and epigenetic factors [14,15]. However, the role of glomerular hyperfiltration early in the course of diabetes lies at the heart of pathophysiology of DN.…”

Section: Pathogenesis Of Dnmentioning

confidence: 99%

Diabetic nephropathy: newer therapeutic perspectives

Keri

Samji

Blumenthal

2018

Journal of Community Hospital Internal Medicine Perspectives

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Diabetic nephropathy (DN is a dreaded consequence of diabetes mellitus, accounting for about 40% of end-stage renal disease (ESRD). It is responsible for significant morbidity and mortality, both directly by causing ESRD and indirectly by increasing cardiovascular risk. Extensive research in this field has thrown light on multiple pathways that can be pharmacologically targeted, to control or reverse the process of DN. Glomerulocentric approach of DN still continues to produce favourable results as evidenced by the recent data on SGLT-2 (sodium glucose co-transporter type 2) inhibitors. Beyond the glomerular mechanisms, numerous novel pathways have been discovered in the last decade. Some of these pathways target inflammatory and oxidative damage, while the others target more specific mechanisms such as AGE-RAGE (advanced glycation end products-receptors for advanced glycation end products), ASK (apoptotic signal-regulating kinase), and endothelin-associated pathways. As a result of the research, a handful of clinically relevant drugs have made it to the human trials which have been elucidated in the following review, bearing in the mind that there are many more to come over the next few years. Ongoing research is expected to inform the clinicians regarding the use of the newer drugs in DN.Abbreviations: USFDA: Unites States Food and Drug Administration; SGLT-2: Sodium glucose transporter type 2; GLP-1: Glucagon-like peptide-1; DDP-4: Dipeptidyl peptidase-4; UACR: urinary albumin creatinine ratio; eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; DN: Diabetic nephropathy; TGF: Tubuloglomerular feedback; RAAS: Renin angiotensin aldosterone system; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; RCT: Randomized controlled trial; AGE-RAGE: Advanced glycation end products-receptors for advanced glycation end products; ASK-1: Apoptotic signal-regulating kinase-1; Nrf-2: Nuclear 1 factor [erythroid derived-2]-related factor 2; ml/min/1.73m2: Millilitre/minute/1.73 square meters of body surface area; ~: Approximately.

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Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets

Cited by 116 publications

References 126 publications

High-Mobility Group Nucleosome-Binding Protein 1 Mediates Renal Fibrosis Correlating with Macrophages Accumulation and Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy Mice Model

High-Mobility Group Nucleosome-Binding Protein 1 Mediates Renal Fibrosis Correlating with Macrophages Accumulation and Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy Mice Model

The Effect of Endoplasmic Reticulum Stress on Podocyte Apoptosis in Diabetic Nephropathy

Diabetic nephropathy: newer therapeutic perspectives

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