Identification of putative androgen-regulated biomarkers of acute kidney injury (AKI) in male and female pig kidneys and validation in human proximal tubule derived epithelial cells (PTEC) models.

2019 edition

Stéphane Nemours

Kidney diseases are a global public health problem that is reaching epidemic proportions. It is now recognized that cumulative episodes of acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and, conversely, that CKD is a risk factor for AKI. Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), being the proximal tubule the primary sensor and effector in the progression of CKD as well as AKI.  Current understanding of progression from AKI to CKD is focused on signaling that promotes tubular atrophy, fibroblast proliferation, and collagen deposition, a result of “failed differentiation” of regenerating tubules. Men are more prone to AKI and to CKD than women and it is accepted that androgens might play a role in these processes. The molecular mechanisms involved in regeneration and the impact of gender remain to be fully elucidated. We postulated that the identification of differentially expressed genes in male and female pig kidney in basal, after injury and upon recovery, based in the urea and creatinine blood levels, could unravel genes and pathways useful to understand the different outcomes observed in men and women. Renal IRI was performed in female and male pigs and mice to identify genes of translational relevance for humans that could be eventually studied in mouse models. Pre-ischemic, ischemic and post-ischemic kidney tissues from male and female pigs were collected for microarray assays and systems biology-based mathematical models were conducted to identify injury/recovery pathways that might be modulated in a sex-dependent manner. In order to validate targets from these pathways, we have developed a model of human PTEC stimulated with dihydrotestosterone (DHT) and subjected to conditions mimicking ischemia/reperfusion in pigs and mice. In these models, we have been able to evaluate, at the mRNA and protein levels, the androgenic regulation of some of the targets of interest that exhibited sexual dimorphism in the pig model. Since there are studies strongly supporting that proximal tubular injury alone can lead to a cascade of events, resulting in peritubular inflammation, interstitial fibrosis, and glomerulosclerosis, we are currently developing PTEC and PBMC (peripheral blood mononuclear cells) co-cultures in order to establish conditions for T cell activation by injured PTEC, to further characterize the role of our targets of interest in the inflammatory responses that precede fibrosis.

This work was supported in part by grants from Ministerio de Economía y Competitividad (SAF2014-59945-R and SAF2017-89989-R to A. Meseguer) and Red de Investigación Renal REDinREN (12/0021/0013 to A. Meseguer).Meseguer’s research group holds the Quality Mention from the Generalitat de Catalunya (2014 SGR).