Over the current funding period, we have demonstrated that hyperhomocysteinemia (hHcys) is a pathogenic factor independent of elevated arterial pressure to initiate or promote the development of glomerular sclerosis associated with hypertension. This pathogenic action of hHcys was found to be attributed to a local oxidative stress associated with Rac-NAD(P)H oxidase (Rac-NOX) activation at the early stage of hHcys. This proposal attempts to further explore the cell and molecular mechanisms by which Hcys sequentially activates Rac-GTPase and NOX and thereby produce glomerular injury. In preliminary studies, we found that Vav2 and Vav3, two guanine nucleotide exchange factors (GEF) that are selectively expressed in rat glomeruli, are responsible for Hcys-induced activation of Rac-GTPase and NOX. Blockade of Vav2 expression or activity significantly reduced glomerular oxidative stress and sclerosis. Therefore, we hypothesized that the GEF Vav as a target signaling molecule of Hcys activates Rac- NOX and thereby triggers the cascade of glomerular injury and sclerosis including local oxidative stress, podocytes dysfunction, ECM deposition and fibrosis. This Vav-triggered signaling contributes to hHcys-induced glomerular injury independent of elevation of arterial pressure in Dahl S (DS) hypertensive rats. To test this hypothesis, three specific Aims are proposed.
Specific Aim 1 will explore the mechanism by which Hcys induces a sequential activation of Rac-GTPase and NOX via Vav-mediated signaling pathway. Different glomerular cells including endothelial cells, mesangial cells and podocytes will be used to dissect the action site of Hcys.
Specific Aim 2 will determine whether Vav- mediated activation of Rac-NOX contributes to glomerular injury or sclerosis in a rat model with experimental hHcys induced by folate-free diet and to explore related mechanisms responsible for increases in Vav activity in this animal model.
Specific Aim 3 will address the contribution of Vav-activated Rac-NOX signaling pathway to glomerular injury independent of elevated arterial pressure in DS rats by servo-control of renal perfusion pressure. These proposed studies, when completed, will for the first time link hHcys-induced glomerular injury with Vav-mediated redox signaling mechanism. An understanding of the mechanism responsible for the DS trait could shed light on the human condition, in particular, on the high susceptibility to end-stage renal disease in African American populations.
Elevations of plasma homocysteine (Hcys), a toxic amino acid, are demonstrated to cause renal dysfunction and chronic renal failure. This project attempts to determine how Hcys produces injury to the kidney, focusing on a novel targeting molecule, Vav protein. Clarification of the action of this protein will help develop new therapeutic strategy for prevention and treatment of Hcys-induced chronic renal failure.
|Boini, Krishna M; Xia, Min; Koka, Saisudha et al. (2016) Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: role of acid sphingomyelinase gene. Oncotarget 7:19031-44|
|Li, Guangbi; Xia, Min; Abais, Justine M et al. (2016) Protective Action of Anandamide and Its COX-2 Metabolite against l-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes. J Pharmacol Exp Ther 358:61-70|
|Xia, Min; Abais, Justine M; Koka, Saisudha et al. (2016) Characterization and Activation of NLRP3 Inflammasomes in the Renal Medulla in Mice. Kidney Blood Press Res 41:208-21|
|Li, Pin-Lan (2015) Cardiovascular pathobiology of inflammasomes: inflammatory machinery and beyond. Antioxid Redox Signal 22:1079-83|
|Li, Guangbi; Li, Cai-Xia; Xia, Min et al. (2015) Enhanced epithelial-to-mesenchymal transition associated with lysosome dysfunction in podocytes: role of p62/Sequestosome 1 as a signaling hub. Cell Physiol Biochem 35:1773-86|
|Abais, Justine M; Xia, Min; Zhang, Yang et al. (2015) Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal 22:1111-29|
|Hu, Junping; Zhu, Qing; Li, Pin-Lan et al. (2015) Stem cell conditioned culture media attenuated albumin-induced epithelial-mesenchymal transition in renal tubular cells. Cell Physiol Biochem 35:1719-28|
|Abais, Justine M; Xia, Min; Li, Guangbi et al. (2014) Contribution of endogenously produced reactive oxygen species to the activation of podocyte NLRP3 inflammasomes in hyperhomocysteinemia. Free Radic Biol Med 67:211-20|
|Wang, Zhengchao; Zhu, Qing; Li, Pin-Lan et al. (2014) Silencing of hypoxia-inducible factor-1Î± gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol 306:F1236-42|
|Hu, Junping; Zhu, Qing; Xia, Min et al. (2014) Transplantation of mesenchymal stem cells into the renal medulla attenuated salt-sensitive hypertension in Dahl S rat. J Mol Med (Berl) 92:1139-45|
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