New Targets for End-Stage Chronic Kidney Disease Therapy

Abstract

Severe forms of chronic kidney disease can lead to a critical, end-stage condition, requiring renal replacement therapy, which may involve a form of dialysis or renal transplantation. Identification and characterization of novel markers and/or targets of therapy that could be applied in these critically ill patients remains the focus of the current research in the field of critical care medicine and has been the objective of our studies for some years past. To this end, we used models of renal vascular disease, Ang II, L-NAME or mice overexpressing renin, treated with AT1 antagonists at different stages of progression, to create cohorts of animals during progression, reversal or escape from therapy. Transcriptomic analysis and comparisons were performed and genes were selected according to the following criteria: a) not previously described in the kidney, b) highly upregulated during progression and returning to the normal levels during reversal, and c) producing proteins that are either circulating or membrane receptors. The involvement of the selected genes in the mechanisms of renal disease was confirmed in additional models of renal disease, initiated in other compartments of the kidney such as glomeruli (administration of nephrotoxic serum) or the tubular interstitium (unilateral ureteral obstruction). The potential of the therapy was tested using mice lacking the expression of these genes and by in vivo administration of antisense oligonucleotides which blocked the transcription of the targeted genes. This strategy allowed the identification of periostin, an extracellular matrix protein normally involved in bone and tooth development, in addition to the discoidin domain receptor1 (DDR1) as potential targets of therapy against renal inflammation and fibrosis.

NFκB-Induced Periostin Activates Integrin-β3 Signaling to Promote Renal Injury in GN

“…Periostin, a matricellular protein associated with mesenchymal phenotype and fibrous structures, was found by us and other investigators to be highly induced in the kidney in several types of renal disease, both in animal models and patient biopsies. 16,17 Nevertheless, the mechanism(s) of induction and the actual role of periostin during disease progression have not been examined. This study aimed to unravel these mechanisms in an established model of NTS-induced renal disease.…”

“…17 Briefly, cells were maintained in RPMI 1640 medium supplemented with 10% FBS, 100 U/ml penicillin streptomycin, and 10 U/ml recombinant mouse INFg (Peprotech) to induce synthesis of the immortalizing T antigen at 33°C and 5% CO 2 . To initiate differentiation, cells were trypsinized and thermoshifted to 37°C in medium without INFg for 10-15 days.…”