Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury.
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.
Faulhaber-Walter
Robert
R
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.
Chen
Limeng
L
Oppermann
Mona
M
Kim
Soo Mi
SM
Huang
Yuning
Y
Hiramatsu
Noriyuki
N
Mizel
Diane
D
Kajiyama
Hiroshi
H
Zerfas
Patricia
P
Briggs
Josephine P
JP
Kopp
Jeffrey B
JB
Schnermann
Jurgen
J
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*
D043682:Receptor, Adenosine A1