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      Rac1 GTPase Inhibition Blocked Podocyte Injury and Glomerular Sclerosis during Hyperhomocysteinemia via Suppression of Nucleotide-Binding Oligomerization Domain-Like Receptor Containing Pyrin Domain 3 Inflammasome Activation

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          Abstract

          Elevated homocysteine (Hcy) levels have been shown to activate nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome leading to podocyte dysfunction and glomerular injury. However, it remains unclear how this inflammasome activation in podocytes is a therapeutic target for reversal of glomerular injury and ultimate sclerosis. The present study tested whether inhibition of Rac1 GTPase activity suppresses NLRP3 inflammation activation and thereby blocks podocyte injury induced by elevated Hcy. In cultured podocytes, we found that L-Hcy (the active Hcy form) stimulated the NLRP3 inflammasome formation, as shown by increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1, which was accompanied by increased interleukin-1β production and caspase-1 activity, indicating NLRP3 inflammasome activation. Rac1 activator, uridine triphosphate (UTP), mimicked L-Hcy-induced NLRP3 inflammasome activation, while Rac1 inhibitor NSC23766 blocked it. This Rac1 inhibition also prevented L-Hcy-induced podocyte dysfunction. All these effects were shown to be mediated via lipid raft redox signaling platforms with nicotinamide adenine dinucleotide phosphate oxidase subunits and consequent O 2 production. In animal studies, hyperhomocysteinemia (hHcy) induced by folate-free diet was shown to induce NLRP3 inflammasome formation and activation in glomeruli, which was also mimicked by UTP and inhibited by NSC23766 to a comparable level seen in Nlrp3 gene knockout mice. These results together suggest that Rac1 inhibition protects the kidney from hHcy-induced podocyte injury and glomerular sclerosis due to its action to suppress NLRP3 inflammasome activation in podocytes.

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          Most cited references 28

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          The inflammasomes: guardians of the body.

          The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.
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            Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats.

            Hypertension frequently accompanies chronic glomerulonephritis. Mesangial injury and glomerulosclerosis are common in glomerulonephritis and are often harbingers of progressive glomerular destruction. Thus, in a model of mesangial immune injury we studied the relationship between hypertension, mesangial injury, and glomerulosclerosis. We induced mesangial ferritin-antiferritin immune complex disease (FIC) in Dahl salt-sensitive (S) and salt-resistant (R) rats. S and R rats with FIC were fed chow containing 0.3% NaCl until 14 weeks of age and then switched to 8.0% NaCl chow until 28 weeks of age. Groups of control S and R rats (no FIC) were either fed 0.3% NaCl for 28 weeks or switched to 8.0% NaCl chow at 14 weeks of age. Blood pressure, serum creatinine, urinary protein, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined at 14 and 28 weeks of age. R rats with or without FIC did not develop hypertension; mesangial injury was minimal. At 14 weeks of age, only S FIC rats developed hypertension, proteinuria, significant mesangial expansion and early glomerulosclerosis. At 28 weeks of age, proteinuria, mesangial expansion, and glomerulosclerosis were significantly more severe in hypertensive S rats with FIC than in those without FIC. These studies show that despite a normal salt intake, mesangial injury hastened the onset of hypertension, but only in rats genetically predisposed to hypertension (S FIC at 14 weeks). High dietary salt further aggravated hypertension, which, in turn, magnified both mesangial injury and glomerulosclerosis. Clinically, the different rates of progression of human glomerulonephritis associated with hypertension may be in part dependent on similar mechanisms.
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              Activation of Nod-like receptor protein 3 inflammasomes turns on podocyte injury and glomerular sclerosis in hyperhomocysteinemia.

              Inflammasome is a multiprotein complex consisting of Nod-like receptor protein 3 (NALP3), apoptosis-associated speck-like protein (ASC), and caspase 1 or 5, which functions to switch on the inflammatory process. The present study hypothesized that the formation and activation of NALP3 inflammasomes turn on podocyte injury leading to glomerulosclerosis during hyperhomocysteinemia (hHcys). RT-PCR and Western blot analysis demonstrated that murine podocytes expressed 3 essential components of the NALP3 inflammasome complex, namely, NALP3, ASC, and caspase 1. Treatment of podocytes with l-homocysteine induced the formation of NALP3 inflammasome complex, an increase in caspase 1 activity, podocyte cytoskeleton rearrangement, and decreased production of vascular endothelial growth factor from podocytes, which were all blocked by silencing the ASC gene or inhibiting caspase 1 activity. In mice with hHcys induced by feeding them a folate-free diet, NALP3 inflammasome formation and activation in glomerular podocytes were detected at an early stage, as shown by confocal microscopy, size exclusion chromatography of the assembled inflammasome complex, and increased interleukin-1β production in glomeruli. Locally silencing the ASC gene in the kidney significantly reduced NALP3 inflammasome formation and interleukin 1β production in glomeruli of mice with hHcys. Pathologically, hHcys-associated albuminuria, foot process effacement of podocytes, loss of podocyte slit diaphragm molecules, and glomerulosclerosis at the late stage were significantly improved by local ASC gene silencing or by caspase 1 inhibition. In conclusion, NALP3 inflammasome formation and activation on stimulation of homocysteine are important molecular mechanisms triggering podocyte injury and ultimately resulting in glomerulosclerosis in hHcys.
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                Author and article information

                Journal
                9610505
                20395
                Kidney Blood Press Res
                Kidney Blood Press. Res.
                Kidney & blood pressure research
                1420-4096
                1423-0143
                11 October 2019
                02 July 2019
                2019
                02 July 2020
                : 44
                : 4
                : 513-532
                Affiliations
                Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
                Author notes
                Pin-Lan Li, MD, PhD, Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (USA), pin-lan.li@ 123456vcuhealth.org
                Article
                NIHMS1054409
                10.1159/000500457
                6800118
                31266025

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense).

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