title: Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury.
abstract: Intraglomerular hypertension and glomerular hyperfiltration likely contribute to the pathogenesis of diabetic nephropathy, and tubuloglomerular feedback (TGF) has been suggested to play a role in diabetic hyperfiltration. A1 adenosine receptor (A1AR) null mice lack a TGF response, so this model was used to investigate the contribution of TGF to hyperfiltration in diabetic Ins2(+/-) Akita mice. TGF responses in Ins2(+/-) A1AR(-/-) double mutants were abolished, whereas they were attenuated in Ins2(+/-) mice. GFR, assessed at 14, 24, and 33 wk, was approximately 30% higher in Ins2(+/-) than in wild-type (WT) mice and increased further in Ins2(+/-) A1AR(-/-) mutants (P < 0.01 versus both WT and Ins2(+/-) mice at all ages). Histologic evidence of glomerular injury and urinary albumin excretion were more pronounced in double-mutant than single-mutant or WT mice. In summary, the marked elevation of GFR in diabetic mice that lack a TGF response indicates that TGF is not required to cause hyperfiltration in the Akita model of diabetes. Rather, an A1AR-dependent mechanism, possibly TGF, limits the degree of diabetic hyperfiltration and nephropathy.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 4D51, 10 Center Drive, MSC 1370, Bethesda, MD 20892, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Faulhaber-Walter
authors.forename: Limeng
authors.initials: L
authors.lastname: Chen
authors.forename: Mona
authors.initials: M
authors.lastname: Oppermann
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Yuning
authors.initials: Y
authors.lastname: Huang
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Diane
authors.initials: D
authors.lastname: Mizel
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajiyama
authors.forename: Patricia
authors.initials: P
authors.lastname: Zerfas
authors.forename: Josephine P
authors.initials: JP
authors.lastname: Briggs
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000209:etiology*; D005919:Glomerular Filtration Rate; D007678:Kidney Glomerulus; D051379:Mice; D043682:Receptor, Adenosine A1 / Q000172:deficiency*
chemical_list: D043682:Receptor, Adenosine A1