SP375
LOXL2 AS A POTENTIAL TREATMENT TARGET IN DIABETIC NEPHROPATHY Free

Introduction and Aims: Fibrotic changes in diabetic nephropathy arise from disorganised and exaggerated deposition of extracellular matrix (ECM) and loss of normal renal parenchyma. Lysyl oxidase-like 2 (LOXL2) is a copper-dependent amine oxidase that belongs to the lysyl oxidase family. LOXL2 plays a key role in ECM stabilisation and is upregulated in many diseases with fibrotic response, primarily by facilitating collagen cross-linking. In addition, it has been linked to fibroblast activation and epithelial to mesenchymal transition (EMT). Increased LOXL2 levels have been found in kidney biopsies of patients with diabetic nephropathy. Thus, targeting LOXL2 might be a useful treatment strategy to prevent fibrogenesis and progression of diabetic nephropathy.

Methods: Diabetes was induced in endothelial nitric oxide synthase (eNOS) knockout mice using streptozotocin. Diabetic mice were treated with a highly selective small molecule LOXL2 inhibitor and/or the angiotensin receptor blocker Telmisartan as comparative limb of current best practice. Renal outcomes were compared to untreated diabetic mice. Urine and kidneys were collected after 24 weeks of treatment and examined for albuminuria and renal histology. The cortical expression of Fibronectin, Collagen I, aSMA, the EMT markers E-Cadherin and Snail as well as the inflammatory markers MCP-1 and F4/80 were examined by real-time PCR and/or immunohistochemistry.

Results: Diabetic mice had increased urinary albumin/creatinine ratios that were significantly attenuated by the LOXL2 inhibitor as well as Telmisartan. LOXL2 inhibition significantly reduced glomerulosclerosis in the diabetic group with further reduction when both treatments were combined. There was reduction of Collagen I, Fibronectin and aSMA by immunohistochemistry in diabetic mice treated with either the LOXL2 inhibitor or Telmisartan. Targeting LOXL2 had no effect on the upregulation of inflammatory markers observed in the diabetic animals.

Conclusions: LOXL2 inhibition had a beneficial effect on preserving glomerular structure and function in a mouse model of diabetic nephropathy. Thus, it might be a potential therapeutic target in diabetic nephropathy.