Tubular reabsorption and diabetes-induced glomerular hyperfiltration.
Elevated glomerular filtration rate (GFR) is a common observation in early diabetes mellitus and closely correlates with the progression of diabetic nephropathy. Hyperfiltration has been explained to be the result of a reduced load of sodium and chloride passing macula densa, secondarily to an increased proximal reabsorption of glucose and sodium by the sodium-glucose co-transporters. This results in an inactivation of the tubuloglomerular feedback (TGF), leading to a reduced afferent arteriolar vasoconstriction and subsequently an increase in GFR. This hypothesis has recently been questioned due to the observation that adenosine A(1)-receptor knockout mice, previously shown to lack a functional TGF mechanism, still display a pronounced hyperfiltration when diabetes is induced. Leyssac demonstrated in the 1960s (Acta Physiol Scand58, 1963:236) that GFR and proximal reabsorption can work independently of each other. Furthermore, by the use of micropuncture technique a reduced hydrostatic pressure in Bowman's space or in the proximal tubule of diabetic rats has been observed. A reduced pressure in Bowman's space will increase the pressure gradient over the filtration barrier and can contribute to the development of diabetic hyperfiltration. When inhibiting proximal reabsorption with a carbonic anhydrase inhibitor, GFR decreases and proximal tubular pressure increases. Measuring intratubular pressure allows a sufficient time resolution to reveal that net filtration pressure decreases before TGF is activated which highlights the importance of intratubular pressure as a regulator of GFR. Taken together, these results imply that the reduced intratubular pressure observed in diabetes might be crucial for the development of glomerular hyperfiltration.
Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
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D000042:Absorption; D000818:Animals; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D025461:Feedback, Physiological; D005919:Glomerular Filtration Rate; D006439:Hemodynamics; D006801:Humans; D006874:Hydrostatic Pressure; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D015854:Up-Regulation