Received June 29, 2007
Accepted on November 15, 2007

BASIC RESEARCH

Lack of A1 Adenosine Receptors Augments Diabetic Hyperfiltration and Glomerular Injury

Robert Faulhaber-Walter ^*, Limeng Chen ^*, Mona Oppermann ^*, Soo Mi Kim ^*, Yuning Huang ^*, Noriyuki Hiramatsu ^*, Diane Mizel ^*, Hiroshi Kajiyama ^*, Patricia Zerfas , Josephine P. Briggs , Jeffrey B. Kopp ^*, and Jurgen Schnermann ^*1

*National Institute of Diabetes and Digestive and Kidney Diseases and Veterinary Resources Program, Office of the Director, National Institutes of Health, Bethesda, and Howard Hughes Medical Institute, Chevy Chase, Maryland

¹ To whom correspondence should be addressed. E-mail: jurgens{at}intra.niddk.nih.gov.

	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.