The current study aimed to understand the role of novel, highly selective, orally active, non-peptide Angiotensin II type 2 receptor (AT2R) agonist, Compound 21 and its potential additive effect with Telmisartan on apoptosis and underlying posttranslational modifications in a non-genetic murine model for type 2 diabetic nephropathy (T2DN). An experimental model for T2DN was developed by administering low dose Streptozotocin in high fat diet fed male Wistar rats, followed by their treatment with Telmisartan, C21 or their combination. Our results demonstrated that C21 and Telmisartan combination attenuated metabolic and renal dysfunction, renal morphological and micro-architectural aberrations and hemodynamic disturbances in type 2 diabetic rats. The anti-apoptotic and anti-inflammatory effects of Telmisartan were significantly accentuated by C21 indicated by expression of apoptotic markers (Parpl, Caspase 8, Caspase 7, cleaved PARP and cleaved Caspase 3) and NF-kappa B mediated inflammatory molecules like interleukin 6, tumour necrosis factor alpha; monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1. C21 was found to improve Telmisartan mediated reversal of histone H3 acetylation at lysine 14 and 27 and expression of histone acetyl transferase, p300/CBP-associated factor also known to regulate NF-kappa B activity and DNA damage response. C21 in combination with Telmisartan markedly mitigates caspase mediated apoptosis and NF-kappa B signalling in T2D kidney, which could be partially attributed to its influence on PCAF mediated histone H3 acetylation. Hence further research should be done to develop this combination to treat T2DN. (C) 2017 Elsevier Inc. All rights reserved.