30/09/2015 1

EPIGENETICS OF KIDNEY DISEASES

Presented By – RAHUL KUMAR M.Pharm (Pharmaeutics)

BITS PILANI 2014H146211P

2

3

Learning Objectives• What is epigenetics?• Epigenetic Modification• DNA Methylation • Role of DNA Methylation in kidney disease• Why to study epigenetics CKD?

4

EPIGENETICS• Epigenetics refers study of heritable changes in gene expression and

phenotype that are not mediated by alteration in the underlying DNA sequence of the genome.• Such as • DNA Methylation• Histone Protein Post Transitional Modification

5

DNA Methylation• DNA methylation is necessary for gene silencing• Enzyme used methyl transferase -DCM (eukaryotes) and DAM

(prokaryotes) • Methyl group is obtain from SAM (S- Adenosyl methionine)• DNA Methylation prevent gene expression• CpG islands are hotspot for DNA Methylation

6

7

Role of DNA Methylation in CKD & DN• HG – Hyperglycaemia• TGF-ß Transforming Growth Factor• DNMT • KLF4 Krupple like factor• SIRT 1 -Sirtuin 1• TF Transcription factor• HMT Histone methyl transferase• HAT Histone methyl transferase

HG – HyperglycaemiaTGF-ß Transforming Growth FactorDNMT KLF4 Krupple like factorSIRT 1 -Sirtuin 1TF Transcription factorHMT Histone methyl transferaseHAT Histone acetyl transferase

8

• DNAme can regulate genes associated with CKD in various renal cells

• DNMT 3A & DNMT 3B genes are essential for de-novo methylation

• UNC13B gene expression in cortical epithelial cells of kidney upregulated by hyperglycaemia , increase expression of UNC13B gene leads to apoptosis and contributes to renal complications to hyperglycaemia • TGF ß induce expression of PAI 1 (plasminogen activator inhibitor 1 )

contribute to fibrosis

9

• In fibroblast, the profibrotic TGF ß can promote fibrosis by inhibiting RASAL 1 expression (negative regulator of ras) through promotor hypermethylation leading to generation of fibrosis.• Produces reactive species causes damage to cells• TGF ß promotes SMAD 3 expression (-) wound healing• In normal kidney, KLF 4 regulates DNAme to increase nephrin

expression in podocytes

10

• However, inhibition of KLF 4 expression in disease conditions increases DNAme and inhibit nephrin expression leading to podocyte apoptosis• In contrast, metabolites generated by SIRT 1 in normal epithelial cells

promotes claudin- 1 expression in glomerular podocytes via promotor hyper- methylation.• SIRT 1 downregulation under diabetic condition relieves this

repression leading to claudin 1 expression and glomerular dysfunction

11

Why to study epigenetic of Kidney ?

• To discover new and better treatments• More selective and specific agents• Eg. HDAC Inhibitors DNMT Inhibitors (under study) Many more to come…………………

12