Novel Therapeutic Approaches for Amelioration of Renal Fibrosis

Abstract

[Chronic kidney disease (CKD) is one of the highly prevalent pathological conditions affecting developing as well as developed countries and has become great burden for the global health sector. However, most of the cases of CKD remain undiagnosed until it progresses to advanced stages. The advanced stages of CKD are almost ubiquitously associated with excessive extracellular matrix (ECM) remodelling in the kidneys. Abnormal ECM remodelling results in establishment of abnormally crosslinked collagen-rich matrix which is resistant to degradation and progresses to fibrotic milieu. Renal fibrosis is one of the most common pathological conditions associated with all forms of CKDs irrespective of the etiological cause. There are multiple mechanisms involved in the renal fibrosis involving inflammation, transforming growth factor-and#946; (TGF- and#946;)/Smad signalling, epithelial-mesenchymal transition (EMT), reduced angiogenic response and pericyte detachment. In the current dissertation work, we first focused on abnormal vasculature in the fibrotic kidney to leverage this abnormality to treat renal fibrosis using a nanomaterial. Cerium oxide nanoparticles were found to preferentially accumulate in the fibrotic kidney primarily due to leaky nature of the blood vessels of fibrotic kidney. The nanoparticles significantly reduced inflammation, oxidative stress, EMT program and TGF-and#946;/Smad signalling in the fibrotic kidneys. Lysyl oxidase (LOX) family of enzymes comprises of five related enzymes primarily responsible for the crosslinking of collagen molecules. The aberrant regulation of these enzymes results in establishment of dense ECM leading to formation of fibrotic foci in different organs. We investigated the role of LOX proteins in the fibrotic kidneys to explore the possibility, whether or not, targeting LOX could reduce the fibrogenesis. We demonstrated that inhibition of LOX proteins significantly reduced renal fibrosis by inhibiting CD44-mediated pericyte detachment.