scholarly journals Histone Deacetylase Inhibitors and Diabetic Kidney Disease

2018 ◽  
Vol 19 (9) ◽  
pp. 2630 ◽  
Author(s):  
Mitchell Hadden ◽  
Andrew Advani

Despite recent clinical trial advances and improvements in clinical care, kidney disease due to diabetes remains the most common cause of chronic kidney failure worldwide. In the search for new treatments, recent attentions have turned to drug repurposing opportunities, including study of the histone deacetylase (HDAC) inhibitor class of agents. HDACs are a group of enzymes that remove functional acetyl groups from histone and non-histone proteins and they can affect cellular function through both epigenetic and non-epigenetic means. Over the past decade, several HDAC inhibitors have been adopted into clinical practice, primarily for the treatment of hematological malignancy, whereas other existing therapies (for instance valproate) have been found to have HDAC inhibitory effects. Here we review the current HDAC inhibitors in the clinic and under development; the literature evidence supporting the renoprotective effects of HDAC inhibitors in experimental diabetic kidney disease; and the adverse effect profiles that may prevent existing therapies from entering the clinic for this indication. Whereas recent research efforts have shed light on the fundamental actions of HDACs in the diabetic kidney, whether these efforts will translate into novel therapies for patients will require more specific and better-tolerated therapies.

2007 ◽  
Vol 7 (4) ◽  
pp. 172-182 ◽  
Author(s):  
Kevin J Hardy ◽  
Niall J Furlong ◽  
Shirley A Hulme ◽  
Sarah V O'Brien

2013 ◽  
Vol 97 (1) ◽  
pp. 115-134 ◽  
Author(s):  
Deanna S. Kania ◽  
Cory T. Smith ◽  
Christy L. Nash ◽  
Jasmine D. Gonzalvo ◽  
Andrea Bittner ◽  
...  

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julie Klein ◽  
Cécile Caubet ◽  
Mylène Camus ◽  
Manousos Makridakis ◽  
Colette Denis ◽  
...  

Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.


2020 ◽  
Vol 21 (6) ◽  
pp. 2218 ◽  
Author(s):  
Devang M. Patel ◽  
Madhura Bose ◽  
Mark E. Cooper

The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.


Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1126-P
Author(s):  
HIDDO LAMBERS. HEERSPINK ◽  
PAUL PERCO ◽  
JOHANNES LEIERER ◽  
MICHAEL K. HANSEN ◽  
ANDREAS HEINZEL ◽  
...  

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 526-P
Author(s):  
MARIANA E. GUADALUPE ◽  
GRACIELA B. ALVAREZ CONDO ◽  
FANNY E. VERA LORENTI ◽  
BETTY J. PAZMIÑO GOMEZ ◽  
EDGAR I. RODAS NEIRA ◽  
...  

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 443-P
Author(s):  
YOSHINORI KAKUTANI ◽  
MASANORI EMOTO ◽  
YUKO YAMAZAKI ◽  
KOKA MOTOYAMA ◽  
TOMOAKI MORIOKA ◽  
...  

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 539-P
Author(s):  
YOSHINORI KAKUTANI ◽  
MASANORI EMOTO ◽  
KATSUHITO MORI ◽  
YUKO YAMAZAKI ◽  
AKINOBU OCHI ◽  
...  

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