Effect of Notch activation on the regenerative response to acute renal failure

Abstract

Episodes of acute renal failure (ARF) are not always fully reversible and may lead to chronic disease, due in part to an inadequate regenerative response. The Notch signaling pathway is involved in determining cell fate during development, and tissue maintenance and repair in adult organs. The purpose of this study was to examine the role of the Notch pathway in renal regeneration following ARF. Kidney injury, induced by ischemia-reperfusion, resulted in early activation of the Notch pathway, as evidenced by increased expression of Notch1 and Notch2 intracellular domain (cleaved Notch). The effect of exogenous administration of the Notch ligand Delta-like-4 (DLL4) on recovery from ARF was then studied. Rats were pretreated by intraperitoneal injection of DLL4 or vehicle control. Two days following the last DLL4 dose, ARF was induced by bilateral renal artery clamping for 45 min followed by reperfusion. The severity of renal injury was similar in DLL4 and control rats. Renal recovery was facilitated by DLL4 treatment, as evidenced by faster return of serum creatinine to baseline by 48 h in DLL4-treated rats as against 5 days in vehicle-treated control rats. Cell proliferation was higher in the DLL4-treated group. In conclusion, activation of the Notch pathway occurs following ARF. Pretreatment with the Notch ligand DLL4 enhanced recovery from ARF and represents a potential novel therapeutic option for regenerating the injured kidney.

Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells

“…The early improvement in renal function has been reported in other forms of cytotherapy of AKI (23,24), and this early effect has been cited as reflecting a paracrine action (10). The early activity achieved by cell transfer is clearly desirable, for it is more likely to limit renal damage and subsequent progression to chronic renal failure (8,18). The improved renal function was not derived from improved microvascular flow, which remained unmodified by cell transplantation, in agreement with prior reports derived in another cell transfer system (26).…”

“…More recent comparative work on AKI and renal ontogeny has uncovered shared mechanisms for reparative tubulogenesis and embryonic tubulogenesis (5,27). Accordingly, factors that participate in kidney development have also being tested on AKI, including bone morphogenetic protein (28), glial cell line-derived neutrophic growth factor (25), and notch pathway ligand DLL4 (8). Current work has demonstrated a strong renal inflammatory component following AKI (14), and some have reported that mediators of inflammation could also be beneficial in AKI (4).…”

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

“…There are several examples of developmental signaling pathways that are reactivated in the adult descendants of progenitor cells during injury. Fibroblast growth factor-7, 54 the notch pathway, 55 and Gli1 re-expression 1 are examples of developmental pathways being reactivated during injury in the adult. Wnt4 is expressed in epithelial progenitors during development and is required for tubulogenesis, and Wnt4 is also expressed developmentally in medullary stroma.…”

Survivin Mediates Renal Proximal Tubule Recovery from AKI

“…The Notch pathway-regulated gene expression occurs in both developing and adult kidneys, and Notch signaling pathways are activated in the adult kidney after injury. 10 Recent studies have documented that Hes protein induced by activation of Notch receptor signaling pathways may function as a nonreceptor scaffold protein in the nucleus that can recruit and allow Janus kinase 2 (JAK2) to phosphorylate signal transducers and activators of transcription 3 (STAT3), thereby leading to activation of an STAT3 signaling pathway. 11 Survivin, which is the smallest member of the inhibitor of apoptosis proteins family, is a 16.5 kDa intracellular protein that has been implicated in regulation of apoptosis, cell division, and cell cycle in cancer cells as well as normal tissues through caspasedependent and -independent mechanisms.…”