Imatinib Attenuates Diabetic Nephropathy in Apolipoprotein E-Knockout Mice

Abstract

In the diabetic kidney, clinical as well as experimental observations have shown an upregulation of growth factors such as PDGF. These studies, however, were not designed to address whether upregulation of PDGF is merely a manifestation of diabetic renal injury or whether PDGF plays an active role in the pathophysiology of diabetic nephropathy. The objectives of this study were first to assess whether PDGF-dependent pathways are involved in the development of diabetic nephropathy and second to determine the effects of PDGF receptor antagonism on this disorder and associated molecular and cellular processes. This study used the diabetic apolipoprotein E-knockout (apoE-KO) mouse, a recently described model of accelerated diabetic nephropathy. Diabetes was induced by injection of streptozotocin in 6-wk-old apoE-KO mice.

A New Look at Platelet-Derived Growth Factor in Renal Disease

“…97 In contrast, in all other injury models tested, blockade of the PDGFR tyrosine kinase was beneficial. Thus, imatinib reduced mesangioproliferative changes in experimental glomerulonephritis 131,132 ; mildly ameliorated both renal functional and structural parameters in diabetic apolipoprotein E knockout mice 133 ; improved survival, renal function, and histology in murine lupus 134 ; and prevented chronic allograft nephropathy after rat kidney transplantation. 135 Finally, another PDGF tyrosine kinase inhibitor, AG 1295, mildly delayed the development of interstitial fibrosis in rats with unilateral ureteral obstruction 136 ; however, at least in the case of imatinib, it is not always clear whether the benefit observed related to inhibition of the PDGFR tyrosine kinase or to inhibition of the c-abl kinase, which also contributes to renal interstitial fibrosis.…”

Imatinib

“…decreased macrophage infiltration in the 5/6 nephrectomy nephron reduction model. 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.…”

“…49 In addition, a murine model of diabetes (streptozotocin-treated apoE knockout mice) showed attenuated collagen type I and IV production when given imatinib, a finding associated with reduced expression of PDGF, PDGFR and TGF-b1. 50 Thus, imatinib's inhibition of PDGFR signaling is another potential mechanism whereby imatinib reduces fibrosis.…”

“…8 In the kidney, DDRs are widely expressed in cells such as epithelia, fibroblasts, vascular smooth muscle cells, and mesangial cells. 50 DDRs are potent mediators of inflammation and fibrosis, and DDR1 null mice have reduced collagen accumulation and infiltrating inflammatory cells in both angiotensin II-induced renal injury and the UUO model of fibrosis. 51,52 DDR1 null mice are also protected from lipopolysaccharide-induced shock, confirming its pivotal role as a mediator of inflammation.…”

Imatinib Suppresses Cryoglobulinemia and Secondary Membranoproliferative Glomerulonephritis

“…9,10 The therapeutic benefit of imatinib in animal models of kidney diseases was reported and has largely been attributed to its effect on PDGFR. [11][12][13][14][15][16] It is well established that the PDGF-B and -D isoforms induce glomerular mesangial cell proliferation through engagement of the PDGFR-␤. [17][18][19][20] Furthermore, it has been shown that glomerular cell proliferation and extracellular matrix expansion in TSLP-transgenic (TSLP-Tg) mice are closely associated with enhanced expression of PDGF-B and PDGFR-␤.…”