Fibrosis, Regeneration, and Aging

In this issue of JASN, Iyoda et al.1 report that administration of nilotinib, a second-generation inhibitor of cellular Abelson (c-ABL) kinase, starting at 2 weeks after subtotal nephrectomy decreases glomerular hypertrophy, glomerular sclerosis, tubulointerstitial inflammation, and fibrosis in remnant kidneys and improves renal function and survival. These results are consistent with those obtained with Imatinib, the c-ABL inhibitor prototype, in models of glomerular disease and unilateral ureteral obstruction (UUO). Nilotinib is also effective in animal models of pulmonary2 and hepatic fibrosis.3,4 Iyoda et al. suggest that nilotinib may prove useful in limiting the progression of chronic kidney disease (CKD) to ESRD. Imatinib was approved by the Food and Drug Administration to treat Philadelphia chromosome–positive chronic myeloid leukemia (CML) in 2001 and has been remarkably successful.5 The Philadelphia chromosome contains a constitutively active oncogenic tyrosine kinase (BCR-ABL) created through translocation of a section of human chromosome 9 containing c-ABL with a specific breakpoint cluster region (BCR) on chromosome 22. The second-generation c-ABL inhibitors nilotinib and dasatinib were approved in 2006 for patients who have CML and are experiencing relapse or are intolerant to imatinib. Recent clinical trials comparing nilotinib and dasatinib with imatinib showed superiority of nilotinib and dasatinib compared with imatinib over the first year.5–7 Imatinib, nilotinib, and dasatinib are competitive inhibitors of various tyrosine kinases with different pharmacologic profiles.8,9 Imatinib inhibits discoidin domain receptor 1 (DDR) > PDGF receptor α/β (PDGFR α/β) > stem cell factor (SCF) receptor c-KIT > DDR2 > BCR-ABL1 > colony-stimulating factor 1 receptor (CSF1R). Nilotinib, structurally related to imatinib, and dasatinib, a dual SRC and ABL inhibitor and structurally unrelated to imatinib, are 20 and 300 times more potent against BCR-ABL, respectively. Nilotinib is more potent against DDR1 and 2 and as potent against PDGFRα/β, c-KIT, and CSF1R. Dasatimib is also active against PDGFRβ, c-KIT, other kinases such as lymphocyte-specific kinase, and SRC family tyrosine kinases YES and FYN. The cytokines and tyrosine kinase receptors inhibited by imatinib, nilotinib, and dasatinib are important regulators of the two main mechanisms of tissue injury repair, regeneration and fibrosis. These cytokines and receptors are differentially used during evolution and development but can coexist in mature mammals within the same tissue. Similar cytokines in a cell- and context-specific manner regulate regeneration and fibrosis, but one of the two mechanisms is preferentially used depending on the intensity and persistence of the initial inflammatory response. Fish, salamanders, and larval frogs regenerate lost appendages, but amputation of a limb in a frog after metamorphosis results in formation of a distal pad of scar tissue.10,11 Skin wounds in mammalian fetuses during early stages of gestation heal without scars. This capacity is markedly blunted but not completely lost at more advanced stages of gestation and in mature animals. For example, small skin wounds can heal without scarring, and gingival papillae can regenerate completely if excised. Reduced platelet degranulation and immaturity of the immune system in salamanders, larval frogs, and mammalian embryos limit the accumulation of inflammatory cytokines and allow for expression of genes involved in tissue patterning. In contrast, release of cytokines such as PDGF and TGF-β in the context of a competent immune system results in the infiltration of neutrophils and macrophages and accumulation of proinflammatory cytokines, activating powerful and redundant fibroproliferative pathways. Iyoda et al.1 contend that the beneficial effect of nilotinib on interstitial fibrosis and renal progression is due to inhibition of PDGFR, c-ABL, CSF1R, and T and B cell proliferation. Inhibition of DDR-1 and c-KIT might also play a role. We briefly review how the aforementioned nilotinib targets affect tissue response to injury. The PDGF family consists of homo- or heterodimeric polypeptides (PDGF-AA, AB, BB, CC, and DD) and two receptors, α and β.12,13 PDGF-C binds to the PDGFRα, activates fibroblast proliferation, and promotes interstitial fibrosis, whereas PDGF-B and D bind to PDGFRβ and promote glomerulosclerosis and, secondarily, interstitial scarring.12,13 PDGF-C and PDGFRα are upregulated in interstitial myofibrobasts. Inhibition of PDGFR by an anti–PDGF-C antiserum or a tyrosine kinase inhibitor reduces UUO-induced interstitial fibrosis in rats and mice.14,15 c-ABL is an important downstream effector of noncanonical TGF-β signaling.16 TGF-β isoforms (TGF-β1, TGF-β2, TGF-β3) bind to heterotetrameric type I and type II serine/threonine kinase receptors. Upon formation of the receptor complexes, the constitutively active type II receptor phosphorylates the type I receptor, activating canonical and noncanonical signaling. Canonical signaling involves phosphorylation of Smad2 and Smad3 proteins, which after complexation with Smad4 translocate to the nucleus and modulate gene expression. Noncanonical signaling involves multiple pathways, including phosphatidylinositol-3-kinase (PI3K). Activation of PI3K with focal adhesion kinase 2 acting as an essential scaffold is a branch point for the activation of p21-activated kinase-2–c-ABL and Akt-TORC1 signaling.17 Noncanonical signaling through c-ABL and TORC1 induces fibroblast proliferation, increasing the number of myofibroblast precursors. Of note is that whereas TORC1 inhibition inhibits fibrosis in multiple animal models of renal progression, it delays recovery from ischemia reperfusion injury.18 Canonical Smad2/3 signaling induces transition of fibroblasts into myofibroblasts and accumulation of extracellular matrix proteins. Interestingly, TGF-β1 and TGF-β2 stimulate whereas TGF-β3 inhibits fibrosis