Progression of most nephropathies to end-stage renal disease remains a major problem in nephrology. Thus, delaying the progression of kidney diseases or arresting its course is an essential management goal. Crescentic glomerulonephritis (GN) is a severe and rapidly progressive glomerular disease with a poor prognosis. Macrophages (MF) play an important role in the induction and development of GN and both the magnitude of proteinuria and the percentage of crescentic glomeruli are correlated with the number of MF that infiltrates the glomerulus. Macrophages are linked with the irreversible scarring that leads to end-stage kidney failure. A2A adenosine receptor (A2AR) is an endogenous inhibitor of inflammation that we have found is expressed in MF from nephritic glomeruli. Activation of A2AR prevents glomerular injury in the acute phase of GN. During the progressive phase of established GN, activation of A2AR (as late as day 14 after induction of anti GBM GN) reduces progressive fibrosis. A2AR activation significantly blocked MF infiltrating the glomeruli and suppressed the glomerular expression of thrombospondin-1 (TSP-1) and osteopontin-1 (OPN-1). The hypothesis of this proposal is that MF A2AR activation arrests GN via suppression of MF function. To test our hypothesis we plan to: (1) Determine the contribution of MF A2AR activation in kidney protection in the progressive phase of established GN. To accomplish this aim we will (a) selectively deplete MF during the established phase of anti-GBM GN and;(b) perform adoptive transfer of MF derived from A2AR deficient mice or wild type mice and treat them with A2AR agonist. (2) To identify potential mechanisms for how A2AR activation on MF acts to prevent progressive kidney damage. To accomplish this aim, we will: (a) identify expression of TSP-1 and OPN-1 in A2AR deficient mice and in mice depleted of MF and reconstituted with A2AR deficient and wild type MF and treated with A2AR agonist and;(b) determine if A2AR activation modulates TSP-1 and/or OPN-1 during protection from progressive kidney damage by adoptive transfer of TSP-1 and OPN-1 deficient MF and using nephritic TSP-1 and OPN-1 KO mice plus treatment with A2AR agonist. We believe our studies will provide a conceptual framework for understanding how A2A adenosine receptors effectively suppress chronic inflammation and consequent fibrosis such that they may be used as therapeutic target for progressive fibrosis in kidney disease and in other chronic inflammatory injuries in humans.
We believe that these studies have potential clinical relevance, since most forms of glomerulonephritis progress rapidly to ESRD. Current treatments are limited because blocking established inflammation is extremely difficult. We think that these studies will provide a conceptual framework for understanding how A2A adenosine receptors effectively suppress chronic inflammation and consequent fibrosis such that they may be used as therapeutic target for progressive fibrosis in kidney disease and in other chronic inflammatory injuries in humans.
|Lanaspa, Miguel A; Epperson, L Elaine; Li, Nanxing et al. (2015) Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS One 10:e0123509|
|Truong, Luan D; Trostel, Jessica; Garcia, Gabriela E (2015) Absence of nicotinic acetylcholine receptor Î±7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model. FASEB J 29:3558-70|
|Trostel, Jessica; Garcia, Gabriela E (2015) Endogenous Inhibitors of Kidney Inflammation. J Nephrol Res 1:61-68|
|Lanaspa, Miguel A; Ishimoto, Takuji; Cicerchi, Christina et al. (2014) Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol 25:2526-38|
|Cicerchi, Christina; Li, Nanxing; Kratzer, James et al. (2014) Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB J 28:3339-50|
|Garcia, Gabriela E; Truong, Luan D; Chen, Jiang-Fan et al. (2011) Adenosine A(2A) receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation. Kidney Int 80:378-88|