H2AK119 monoubiquitination regulates Angiotensin II receptor mediated macrophage infiltration and renal fibrosis in type 2 diabetic rats.
Monocyte chemoattractant protein (MCP-1) and transforming growth factor-β (TGF-β1)-markers of inflammation and fibrosis, are central to type 2 diabetic nephropathy (T2DN) progression. The epigenetic basis of their expression has also been explored to certain extent. H2A lysine 119 monoubiquitination (H2AK119Ub), a repressive chromatin mark regulates progression of hyperglycaemia induced fibrosis in glomerular mesangial cells. However, how H2AK119Ub affects the expression of MCP-1 and TGF-β1 and their regulation by Angiotensin II receptor subtypes remains unknown. In the current study, we aimed to study the effect of Angiotensin II receptors' blockade on the macrophage infiltration and histone modifications occurring at the promoter region of Mcp1 and Tgfb1in high fat diet fed and low dose streptozotocin treated male Wistar rats. Hereby, we present the first report delineating a distinct link between H2AK119Ub and macrophage infiltration and fibrosis i.e. the enrichment of H2AUb at Mcp1 and Tgfb1 promoter region was found to reduce drastically in the T2DN which could be significantly reversed by Telmisartan and was further elevated by PD123319. We could conclude that the Angiotensin II mediated macrophage infiltration in T2DN is regulated at least partially by H2AK119Ub through both AT1 and AT2 receptors, which to the best of our knowledge, presents the first report for the regulation of Mcp1 by H2AK119Ub. Thus an approach targeting AT1R blockade and AT2R activation accompanied by an epigenetic modulator may be more suitable to ameliorate the macrophage infiltration and fibrosis associated with T2DN.
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Anuradha
A
Pandey
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Santosh Kumar
SK
Goru
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Almesh
A
Kadakol
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Vajir
V
Malek
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Nisha
N
Sharma
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India. Electronic address: anil.gaikwad@pilani.bits-pilani.ac.in.
Anil Bhanudas
AB
Gaikwad
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D006657:Histones / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077333:Telmisartan; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D006657:Histones; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D053773:Transforming Growth Factor beta1; C073402:PD 123319; D008239:Lysine; D000077333:Telmisartan
Angiotensin II receptors; Fibrosis; H2A lysine 119 monoubiquitination; Macrophage infiltration; Type 2 diabetic nephropathy