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Testing a LOXL2 Inhibitor for Ameliorating Glomerulosclerosis in Diabetic Nephropathy
Diseases of the glomerulus, the filtering unit of the kidney, account for over 60% of all cases of end-stage renal disease (ESRD), a major health problem worldwide. Diabetic nephropathy (DN) is the leading cause of ESRD. Despite current treatments, the development and progression of nephropathy in the patients with diabetes remains unpreventable. As many other progressive kidney diseases, DN is characterized by thickening of glomerular and tubular basal membranes, with progressive mesangial expansion and development of fibrosis. Increased deposition of highly crosslinked collagen IV is known to be one of the main component of fibrotic lesions. Interestingly, the expression of lysyl oxidase like-2 (LOXL2), a member of the lysyl oxidase family, has been reported to be upregulated in kidney biopsies of patients with chronic kidney disease, including DN. We have recently demonstrated that LOXL2 is the main lysyl oxidase isoform of glomerular basal membranes that crosslinks collagen IV. LOXL2 is significantly upregulated in fibrotic glomeruli of diabetic eNOS -/- db/db mice, a type II model of DN, which manifest characteristics reminiscent of type II diabetes in humans. Preliminary studies in cultured podocytes and glomerular endothelial cells suggest that LOXL2 upregulation is driven by TGF-ß stimulation. With the intention to develop strategies that would reduce glomerulosclerosis, we have identified a highly selective LOXL2 inhibitor that efficiently inhibits LOXL2-mediated collagen IV crosslinking in a cell culture system. Thus, we hypothesize that inhibition of LOXL2-mediated collagen IV crosslinking will block or ameliorate the development of glomerulosclerosis in diabetic animals. To test this hypothesis we have designed 3 specific aims. In Aim 1 we will characterize LOXL2 during the course of DN development in eNOs -/- db/db mice. Aim 2 will test the effectiveness of LOXL2 inhibitor (in combination with angiotensin converting enzyme inhibitor (ACEI) or alone) to interfere with glomerulosclerosis in DN animals. Aim 3 is designed to define the molecular mechanisms by which LOXL2 is upregulated by TGF-b1 in glomerular cells. This study would provide the first preclinical evidence for targeting LOXL2 to improve DN therapies. Satisfactory results would be used to initiate funding proposals to study the role of LOXL2 in glomerulosclerosis.
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The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the
External Evaluation Committee
The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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