Testing of a selective integrin inhibitor in a type 1 model of diabetic nephropathy
Chronic Kidney Disease (CKD) affects over 20 million people in the US with treatment of US individuals having end-stage renal disease (ESRD) costing Medicare over $32 billion in 2010. The most frequent causes of ESRD are hypertension and diabetes. Despite treatment of CKD with reno-protective agents, many individuals, particularly those with type 1 diabetes, progress to ESRD. Thus, there is urgent need for an effective treatment for CKD. Irrespective of the cause of CKD, fibrosis is a key underlying feature and plays a major role in progression to ESRD. Fibrosis is characterized by the abnormal deposition of extracellular matrix components including collagen within the glomeruli and along the tubules of the kidneys. The regulation of matrix components depends on many factors, including cell-matrix interactions via integrins. Integrins are transmembrane receptors consisting of an a and ß subunit non-covalently bound. Upon ligand binding, they activate intracellular signaling pathways to control various functions including matrix synthesis/degradation. The integrin we focus on is a collagen receptor and contributes to kidney fibrosis by positively regulating collagen production. In support of this finding, genetic and pharmacological inhibition of this receptor in mice ameliorates kidney fibrosis following adriamycin-mediated injury. These data suggest that inhibition of this receptor might be beneficial in the setting of fibrotic diseases, including diabetic nephropathy (DN). Inhibitors of the integrin of interest have only been used in prevention studies, as treatment was started at the time of kidney injury. The goal of this grant is to evaluate the efficacy of a small-molecule inhibitor of the integrin of interest to slow and ideally halt the progression to diabetes-mediated nephropathy in a mouse model of type 1 diabetes. Positive proof-of-concept will be assessed by reductions in albuminuria, glomerular and interstitial fibrosis, glomerular basement thickening, and improvement of glomerular filtration rate. This study will provide the first preclinical proof-of-concept for inhibitors of this integrin to be efficacious in DN. Positive results will initiate funding proposals for identification and testing of novel inhibitors of this integrin, with properties suitable for clinical development, in preclinical models of DN.

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