Nilotinib Attenuates Renal Injury and Prolongs Survival in Chronic Kidney Disease

Abstract

The tyrosine kinase inhibitor imatinib is beneficial in experimental renal diseases, but the effect of the new tyrosine kinase inhibitor nilotinib on the progression of renal failure is unknown. We administered either nilotinib or vehicle to Sprague-Dawley rats beginning 2 weeks after 5/6 nephrectomy (Nx) or laparotomy and continuing for 8 weeks. Serum creatinine levels were significantly lower in the nilotinib group after 6 and 8 weeks of treatment. Furthermore, nilotinib-treated rats had less proteinuria, attenuated glomerulosclerosis and tubulointerstitial damage, and reduced macrophage infiltration into the tubulointerstitium. Treatment with nilotinib also significantly decreased renal cortical expression of profibrogenic genes, such as IL-1␤ and monocyte chemotactic protein-1, which correlated closely with the tubulointerstitial damage score and ED1-positive macrophages score. In addition, nilotinib treatment significantly prolonged survival. Taken together, these results suggest that nilotinib may limit the progression of chronic kidney disease.

Imatinib

“…50,53,54,[57][58][59] Inflammatory cytokines were decreased by imatinib treatment in the models of anti-GBM and LN and by nilotinib treatment in the 5/6 nephrectomy model. 54,57,59 These findings provide further evidence for the immunomodulatory properties of imatinib and nilotinib. Imatinib also markedly reduced ECM deposition and fibrosis in most of these murine models of kidney disease.…”

“…11,49,50,53,55,[58][59][60][61] PDGF signaling was disrupted by imatinib, as shown by decreased levels of PDGF-A, 58 PDGF-B, 50,58,59 , and PDGFR-b. 50,54,57,58 Imatinib also decreased levels of TGF-b 50,53,54,58,59 and TGF-b type I receptor 58 as well. Therefore, imatinib reduces indices of fibrosis in murine injury models with associated suppression of TGF-b and PDGF signaling, suggesting that imatinib may have beneficial antifibrotic effects in additional to its immunomodulatory properties.…”

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).…”

“…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.…”

“…Thus, fibrosis likely developed to provide a survival advantage to early vertebrates in response to various forms of tissue injury, whereas age-related and fibrotic diseases are the price one pays to protect the survival of the genetic pool. 10,11 Iyoda et al 1 suggest that c-ABL inhibitors might prove clinically useful in limiting the progression of CKD. A number of issues need to be considered regarding the feasibility of translating their observations into clinical trials.…”