Diabetic nephropathy is now the most prevalent cause of end stage renal disease, accounting for 40-50% 1, and apoptosis has been shown to be an important mechanism for tubular atrophy, a sensitive predictor of disease progression. As the submicron vesicles shed from plasma membranes, microparticles (MPs) are found in the urine of healthy humans and rodents and their contents and amounts are altered following cell activation and apoptosis. The overall goal of the proposed studies is to uncover the mechanisms leading to renal secretion of MPs and their role in tubular injury in diabetes. Kidney injury molecule-1 (KIM-1) is a urinary biomarker for renal proximal tubular damage and has been recently identified as a scavenger receptor involved in epithelial phagocytosis. We found that tubular expression of KIM-1 was dramatically increased, in association with proteinuria and kidney injury, in Zucker diabetic fatty rats. In vitro studies using primary cultures of rat and mouse tubular cells revealed that albumin increased expression and vesicular accumulation of KIM-1 as well as its secretion via MP shedding. Moreover, this increase in KIM-1 expression was associated with an elevation of caspase-3 activity. Interestingly, knockdown of KIM-1 confers resistance to epithelial apoptosis as reflected by an up-regulation of bcl-2 and suppression of caspase-3 activation. We conducted additional pilot study indicating that tubular epithelial cells were capable of uptaking MPs and that the internalization of MPs containing KIM-1 (KIM-MPs) disrupted normal tight junction in tubular epithelial monolayer. Therefore, those preliminary results prompted our central hypothesis stating that """"""""KIM-1/KIM- MPs contribute to tubular dysfunction by promoting cell injury and apoptosis"""""""". Specifically, we will address the following aims:
Aim I. To test the hypothesis that tubular expression and secretion of KIM-1 are increased in response to albumin overload. Systematic analyses will be conducted to delineate expression, localization and secretion of KIM-1 in tubular epithelial cells in response to albumin overload and other apoptotic stimuli in both in vivo animal model and in vitro cell culture model.
Aim II. To test the hypothesis that KIM-1/KIM-MPs contribute to tubular cell injury and apoptosis. The effects of KIM-1/KIM-MPs on tubular cell injury and apoptosis in response to albumin and other apoptotic stimuli will be determined by 1) examining the effects of loss- and gain-of-function of KIM-1 on tubular cell injury and apoptosis, 2) delineating the apoptotic pathways by which KIM-1 contributes to tubular cell apoptosis upon apoptotic stimulation, 3) determining the effects of KIM-MPs on the target cells by treating normal tubular epithelial cell monolayer with KIM-1 positive or KIM-1 negative microparticles. Together, the series of studies outlined in Aims I and II will enable us to provide new insights into the functional role of KIM-1/KIM-MPs in tubular injury and dysfunction associated with diabetic kidney disease. Our studies will also shed light on KIM-1/KIM-MPs as attractive targets for kidney disease management.

Public Health Relevance

Diabetic nephropathy is the most common cause of end-stage renal disease. Tubular cell injury and apoptosis are important mechanisms for disease progression. However, the signaling elements and molecular mediators involved in diabetic tubular injury are still unclear. The proposed research will enable us to establish new therapeutic strategies to prevent and treat diabetic kidney disease in humans by examining the role of kidney injury molecule-1 (KIM-1) and KIM-1 containing microparticles in the pathogenesis of tubular injury and dysfunction in diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Pilot Research Project (SC2)
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Special Emphasis Panel (ZGM1-MBRS-9 (SC))
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Agodoa, Lawrence Y
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Morehouse School of Medicine
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Chen, Xiaoming; Cobbs, Alyssa; George, Jasmine et al. (2017) Endocytosis of Albumin Induces Matrix Metalloproteinase-9 by Activating the ERK Signaling Pathway in Renal Tubule Epithelial Cells. Int J Mol Sci 18:
Zhao, Xueying; Jiang, Chen; Olufade, Rebecca et al. (2016) Kidney Injury Molecule-1 Enhances Endocytosis of Albumin in Renal Proximal Tubular Cells. J Cell Physiol 231:896-907
Zhao, Xueying; Zhang, Yuanyuan; Leander, Michelle et al. (2014) Altered expression profile of renal ?(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists. J Diabetes Res 2014:725634