Internal Medicine: Open Access
Open Access
ISSN: 2165-8048
ISSN: 2165-8048
Wenzheng Zhang
Albany Medical College, USA
Posters & Accepted Abstracts: Intern Med
Kidney fibrosis is the hallmark of chronic kidney disease (CKD). Despite aggressive management, CKD often progresses to endstage renal disease which costs the US>$40 billion dollars and >90000 deaths annually. The current main therapy targeting the renin-angiotensin-aldosterone system with drugs including Spironolactone often delays but does not stop the progression. Factors modulating the aldosterone global effect from its primary action-site connecting tubule/collecting duct may prove better targets. However, such genetic and epigenetic factors remain virtually unknown, partially because of the intrinsic limitations of the clinical studies. These limitations include lack of kidney biopsies to verify the status of the disease, impossibility of genetic manipulation in patients to establish the causative relationship and impracticability through mutational analyses with blood DNA to identify somatic mutations, which occur at atypical high rate in human kidney. Our published and preliminary data suggest that patients with diabetic nephropathy and CKD may have mutations in histone H3 K79 methyltransferase hDOT1L and abolished H3 dimethylation in their kidney biopsies; Dot1a (encoded by mouse Dot1l) represses ET1 and other aldosterone target genes. Aldosterone relieves Dot1amediated repression by multiple mechanisms; connecting tubule/collecting duct-specific ablation of Dot1l in Dot1lAC mice causes abolition of H3 dimethylation, up-regulation of endothelin 1 and development of severe kidney fibrosis throughout the whole kidney under various settings. Our study highlights Dot1l as a potential novel renoprotective player and its somatic inactivation in kidney may cause CKD in mice and humans.
Email: zhangw1@mail.amc.edu