Reduction of Carbonyl Stress for the Prevention of Diabetic Kidney Disease
Oxidative stress has long been heralded as an attractive therapeutic option for many diseases including diabetic kidney disease (DKD). Thus, antioxidants have been attempted to treat DKD. However, these strategies to combat oxidative stress involve free radical scavengers which mop up dangerous reactive oxygen species within the cell. These therapies have generally been disappointing for DKD, because the sheer quantity of oxidative stress quelches the ‘antioxidant’ molecules, and does not provide sustained benefit to the patient. A new class of therapeutics developed by the Mochly-Rosen laboratory here at Stanford focuses on activating enzymes present within the body to break down these reactive oxygen species. These types of therapeutics would obviate the need to supply the patient with copious amounts of anti-oxidants because the drug would be stable over time. We have intriguing preliminary data to suggest that one such therapeutic, termed Alda1, can modify a specific enzyme, aldehyde dehydrogenase 2 (ALDH2), within the kidney to prevent the onset of DKD. This work would provide a novel approach to the treatment of this increasingly prevalent disorder. Our specific aims are designed to test the efficacy of Alda1 in diabetic mouse models and to use the drug to directly study the mechanism of oxidative stress-induced damage in cells. These experiments will open the door for further funding to better understand the role of oxidative stress in the kidney and to optimize management of this disorder. The experience of the principal investigator has been in molecular biology and cell signaling, and he will now shift his focus towards understanding and treating DKD. The PI has a previous history of publication in DKD at an earlier stage of training. This prior experience and his clinical background in Nephrology have inspired this new direction for the laboratory to engage this challenging, unmet need in research. The proposed research will be an important step toward developing new therapeutics to prevent DKD, and will be performed in the broader context of a research program dedicated to studying DKD.

The Influence of Esm-1 on Leukocyte Infiltration in Diabetic Nephropathy
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease and end-stage renal disease in the United States and the world, yet there are no therapies to halt or reverse the disease. Several lines of evidence suggest that the immune system contributes significantly to the onset of DN, and limiting the infiltration of pro-inflammatory leukocytes into the kidney may attenuate DN. In this application we will address the use of a natural secreted inhibitor of leukocyte adhesion called endothelial cell-specific molecule-1, Esm1, to disrupt leukocyte : endothelial cell interactions and attenuate diabetic nephropathy (DN). Esm-1 binds to activated leukocyte free antigen-1 (LFA-1) on circulating leukocytes, and blocks LFA-1 : intercellular adhesion molecule (ICAM-1) interaction in a dose-dependent manner. Thus, absence of Esm-1 may promote leukocyte infiltration into the kidney or conversely, increased expression of Esm-1 may suppress immune-mediated injury. Consistent with a protective role for this gene, we found that glomerular Esm-1 levels are decreased with diabetes in a DN-susceptible strain and increased in DN-resistant mice. For this proposal, we hypothesize that Esm-1 protects against DN by attenuating leukocyte infiltration via inhibition of LFA-1: ICAM-1 interaction in glomerular endothelium. For Aim 1, we will perform a dose-response curve for Esm-1 efficacy to inhibit leukocyte adhesion to glomerular endothelial cells in vitro and in vivo. For Aim 2, in order to determine the optimal timing for therapeutic Esm-1 delivery we will evaluate Esm-1 expression in glomeruli from DN-susceptible and DN-resistant mice. For Aim 3, we will induce diabetes in DN-susceptible mice, over-express circulating Esm-1 and determine the contribution of Esm-1 to leukocyte infiltration, albuminuria, and the characteristic histologic changes of DN. There are few proven mechanisms that regulate leukocyte migration and localization within specific tissues. These pilot experiments with Esm-1 would provide novel in vivo evidence for use of local endothelium-derived inhibitors of leukocyte adhesion and provide proof-of-concept for a novel therapeutic strategy for DN and other ICAM-1 dependent kidney diseases.

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