Identification of Novel Therapeutic Approaches to the Progression of Chronic Kidney Disease

Progression of chronic kidney disease (CKD) to renal failure is a substantial international public health problem. Existing treatments have limited effectiveness as they slow, but do not prevent, progression. This is particularly true for rare forms of CKD. Accordingly, we sought to identify and test new therapeutic approaches to Alport syndrome (AS), a rare genetic condition characterized by progressive CKD. AS is caused by mutations in the genes encoding collagen, type IV, alpha (COL4A) chains present in the glomerular basement membrane. Mutations interfere with normal assembly of the COL4A network necessary for maintenance of the glomerular filtration barrier, leading to glomerular injury, proteinuria, and interstitial fibrosis. We studied Col4a3–/– mice, an experimental model displaying these hallmarks of AS. We have reported that intrarenal expression of angiotensin-converting enzyme 2 (ACE2), a peptidase that catalyzes conversion of angiotensin (Ang) II to Ang-(1–7), is decreased in Col4a3–/– mice. We therefore examined effects of recombinant ACE2 (rACE2) administration on kidney injury in Col4a3–/– mice. Treatment with rACE2 affected turnover of renal ACE2 likely through suppression of tumor necrosis factor alpha-converting enzyme. rACE2 also mitigated kidney mitogen-activated protein kinase (MAPK) activation, fibrosis, and oxidative stress. Utilizing an unbiased approach, we defined a disease progression signature reflecting transcript-level expression patterns detected in Col4a3–/– kidneys during development of CKD. We performed computational drug repurposing by querying the Connectivity Map for potential compounds to reverse signature gene expression. Vorinostat, a lysine deacetylase (KDAC) inhibitor emerged as a potential treatment. Vorinostat reduced tubulointerstitial fibrosis and prolonged survival of Col4a3–/– mice. In tubular epithelial cells, vorinostat prevented Ang II- and albumin-induced MAPK phosphorylation and activator protein 1 activation. Taken together, this work identified two novel treatment approaches to AS: rACE2 delivery and KDAC inhibition. These studies also demonstrated that regulation of Ang peptide metabolism and lysine acetylation via ACE2 and KDACs, respectively, are important determinants of disease progression in experimental CKD, at least in part, due to their impact on MAPK signaling and evolution of interstitial fibrosis. This dissertation provides a rationale for rACE2 therapy and KDAC blockade in humans with CKD.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.