title: Inhibition of sodium-linked glucose reabsorption normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A₁-receptor deficient mice.
abstract: OBJECTIVE
  Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. Sustained hyperglycaemia is also closely associated with kidney hypertrophy and increased electrolyte and glucose reabsorption in the proximal tubule. In this study, we investigated the role of the increased tubular sodium/glucose cotransport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback (TGF) mechanism, we used adenosine A₁-receptor deficient (A1AR(-/-)) mice known to lack a functional TGF mechanism and compared the results to corresponding wild-type animals (A1AR(+/+)).
  
  
  METHODS
  Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose cotransporters were inhibited by phlorizin 30 min prior to GFR measurements.
  
  
  RESULTS
  Normoglycaemic animals had a similar GFR independent of genotype (A₁AR(+/+) 233 ± 11 vs. A₁AR(-/-) 241 ± 25 μL min(-1)), and induction of diabetes resulted in glomerular hyperfiltration in both groups (A₁AR(+/+) 380 ± 25 vs. A₁AR(-/-) 336 ± 35 μL min(-1); both P < 0.05). Phlorizin had no effect on GFR in normoglycaemic mice, whereas it reduced GFR in both genotypes during diabetes (A₁AR(+/+) 365 ± 18 to 295 ± 19, A₁AR(-/-) 354 ± 38 to 199 ± 15 μL min(-1); both P < 0.05). Notably, the reduction was more pronounced in the A₁AR(-/-) (P < 0.05).
  
  
  CONCLUSIONS
  This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Sällström
authors.forename: T
authors.initials: T
authors.lastname: Eriksson
authors.forename: B B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: A E G
authors.initials: AE
authors.lastname: Persson
authors.forename: F
authors.initials: F
authors.lastname: Palm
mesh_terms: D000818:Animals; D003243:Consciousness; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D005919:Glomerular Filtration Rate / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043682:Receptor, Adenosine A1 / Q000172:deficiency; D012964:Sodium / Q000378:metabolism*
chemical_list: D043682:Receptor, Adenosine A1; D012964:Sodium; D005947:Glucose
keywords: adenosine; diabetes mellitus; glomerular hyperfiltration; tubuloglomerular feedback
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9407-12
references.pmid: 11470917
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Nov;281(5):R1362-7
references.pmid: 11641103
references.citation: Nitric Oxide. 2004 Sep;11(2):147-55
references.pmid: 15491847
references.citation: Acta Physiol (Oxf). 2007 Jul;190(3):253-9
references.pmid: 17581137
references.citation: Nat Biotechnol. 2012 Oct;30(10):899-900
references.pmid: 23051788
references.citation: Diabetes. 1967 Apr;16(4):264-7
references.pmid: 6023168
references.citation: Endocrinology. 2008 Feb;149(2):717-24
references.pmid: 17962340
references.citation: Pflugers Arch. 2004 Sep;448(6):621-8
references.pmid: 15309539
references.citation: Diabetologia. 1981 Oct;21(4):409-14
references.pmid: 7286501
references.citation: Acta Physiol Scand. 1982 Jan;114(1):1-7
references.pmid: 7136739
references.citation: Am J Nephrol. 2008;28(1):107-14
references.pmid: 17943018
references.citation: Kidney Int. 1981 Mar;19(3):410-5
references.pmid: 7241881
references.citation: Acta Physiol (Oxf). 2010 Sep;200(1):3-10
references.pmid: 20518753
references.citation: J Pharmacol Toxicol Methods. 2013 May-Jun;67(3):187-93
references.pmid: 23376812
references.citation: Am J Physiol Renal Physiol. 2000 Sep;279(3):F573-83
references.pmid: 10966937
references.citation: J Clin Invest. 1986 Jun;77(6):1925-30
references.pmid: 3011862
references.citation: Kidney Int. 1992 Apr;41(4):822-8
references.pmid: 1513104
references.citation: Diabetes. 2005 Dec;54(12):3427-34
references.pmid: 16306358
references.citation: Diabetologia. 2009 Apr;52(4):691-7
references.pmid: 19198800
references.citation: Am J Physiol. 1994 May;266(5 Pt 2):R1544-50
references.pmid: 8203631
references.citation: J Clin Invest. 2001 Jan;107(2):217-24
references.pmid: 11160138
references.citation: J Am Soc Nephrol. 2008 Apr;19(4):722-30
references.pmid: 18256360
references.citation: Scand J Clin Lab Invest. 1971 Sep;28(1):79-90
references.pmid: 5093522
references.citation: J Am Soc Nephrol. 1999 Dec;10(12):2569-76
references.pmid: 10589696
references.citation: Scand J Clin Lab Invest. 1971 Sep;28(1):101-9
references.pmid: 5093515
references.citation: Diabetologia. 1980 Jun;18(6):501-5
references.pmid: 7418959
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9983-8
references.pmid: 11504952
references.citation: Nephron Physiol. 2009;111(3):p30-8
references.pmid: 19276628
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1009-22
references.pmid: 21228342
references.citation: Kidney Int. 1991 Oct;40(4):792-807
references.pmid: 1745032
references.citation: Am J Physiol. 1971 Aug;221(2):394-400
references.pmid: 5560286
references.citation: N Engl J Med. 1984 Jul 12;311(2):89-93
references.pmid: 6738599
references.citation: Clin Exp Pharmacol Physiol. 2004 May-Jun;31(5-6):372-9
references.pmid: 15191416
references.citation: Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F156-67
references.pmid: 23152292
references.citation: Acta Physiol Acad Sci Hung. 1957;12(4):363-71
references.pmid: 13497745