Tubuloglomerular feedback: mechanistic insights from gene-manipulated mice.
Tubuloglomerular feedback (TGF) describes a causal and direct relationship between tubular NaCl concentration at the end of the ascending limb of the loop of Henle and afferent arteriolar tone. The use of genetically altered mice has led to an expansion of our understanding of the mechanisms underlying the functional coupling of epithelial, mesangial, and vascular cells in TGF. Studies in mice with deletions of the A or B isoform of NKCC2 (Na,K,2Cl cotransporter) and of ROMK indicate that NaCl uptake is required for response initiation. A role for transcellular salt transport is suggested by the inhibitory effect of ouabain in mutant mice with an ouabain-sensitive alpha1 Na,K-ATPase. No effect on TGF was observed in NHE2- and H/K-ATPase-deficient mice. TGF responses are abolished in A1 adenosine receptor-deficient mice, and studies in mice with null mutations in NTPDase1 or ecto-5'-nucleotidase indicate that adenosine involved in TGF is mainly derived from dephosphorylation of released ATP. Angiotensin II is a required cofactor for the elicitation of TGF responses, as AT1 receptor or angiotensin-converting enzyme deficiencies reduce TGF responses, mostly by reducing adenosine effectiveness. Overall, the evidence from these studies in genetically altered mice indicates that transcellular NaCl transport induces the generation of adenosine that, in conjunction with angiotensin II, elicits afferent arteriolar constriction.
Schnermann
Jurgen
J
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. jurgens@intra.niddk.nih.gov
Briggs
Josephine P
JP
D000241:Adenosine / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D025461:Feedback, Physiological / Q000502:physiology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000502:physiology*; D007684:Kidney Tubules / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic
D000804:Angiotensin II; D000251:Adenosine Triphosphatases; D000241:Adenosine