Abstract
An increase of glomerular filtration rate (hyperfiltration) is an early functional change associated with type I or type II diabetes mellitus in patients and animal models. The causes underlying glomerular hyperfiltration are not entirely clear. There is evidence from studies in the streptozotocin model of diabetes in rats that an increase of proximal tubular reabsorption results in the withdrawal of a vasoconstrictor input exerted by the tubuloglomerular feedback (TGF) mechanism. In the present study, we have used micropuncture to assess single nephron function in wild type (WT) mice and in two strains of type I diabetic Ins2+/- mice in either a C57Bl/6 (Akita) or an A1AR-/- background (Akita/A1AR-/-) in which TGF is non-functional. Kidney glomerular filtration rate (GFR) of anesthetized mice was increased by 25% in Akita mice and by 52% in Akita/A1AR-/-, but did not differ between genotypes when corrected for kidney weight. Single nephron GFR (SNGFR) measured by end-proximal fluid collections averaged 11.8 ± 1 nl/min (n=17), 13.05 ± 1.1 nl/min (n=23; p=0.27), and 15.4 ± 0.84 nl/min (n=26; p=0.009 compared to WT; p=0.09 compared to Akita) in WT, Akita, and Akita/A1AR-/- mice respectively. Proximal tubular fluid reabsorption was not different between WT and diabetic mice and correlated with SNGFR in all genotypes. We conclude that glomerular hyperfiltration is a primary event in the Akita model of type I diabetes, perhaps driven by an increased filtering surface area, and that it is ameliorated by TGF to the extent that this regulatory system is functional.
Highlights
The development of both type I and type II diabetes mellitus (DM) is often associated with an increase of glomerular filtration rate (GFR), and the same phenomenon has been observed in various experimental models of DM1,2
As we have argued previously, the augmented hyperfiltration cannot be mediated by tubuloglomerular feedback (TGF) since the A1 adenosine receptor (A1AR)-deficiency in both mixed wild type (WT) and Akita diabetic genetic backgrounds renders TGF non-functional9,12,l4
One may assume that Single nephron GFR (SNGFR) is closest to steady-state values in the Akita/A1AR-/- mice in which TGF is non-functional under all circumstances, and that proximal SNGFRs in WT and Akita mice overestimate true filtration rates to probably different degrees
Summary
The development of both type I and type II diabetes mellitus (DM) is often associated with an increase of glomerular filtration rate (GFR) (usually referred to as glomerular hyperfiltration), and the same phenomenon has been observed in various experimental models of DM1,2. One hypothesis argues that the primary process is the growth of the proximal tubule leading to enhanced water and solute reabsorption with the consequence that NaCl delivery to the macula densa decreases, the TGF-imposed vasomotor tone relaxes, and glomerular capillary pressure and GFR increase[6] This “tubulo-centric” concept has been supported by substantial experimental evidence coming for the most part from experiments in rats with streptozotocin-induced type I DM6. It has been suggested that diabetic hyperfiltration is primary, driven by structural changes and/or by largely unknown derangements in the spectrum of vasoactive mediators, and that TGF serves as a mechanism that prevents the full extent of the effects of these abnormalities on GFR7 These two concepts are not reconcilable because vasorelaxation is caused by a normally functioning TGF in the first, whereas, in the second, vasorelaxation is TGF-independent and is counteracted by it to the extent TGF is functional. This “glomerulo-centric” theory has found support in the finding that type I diabetic mice of the Akita strain without a functional TGF system, achieved by breeding the Ins[2] mutation of the Akita mice into the TGF-less A1 adenosine receptor (A1AR) null background[8], display exaggerated hyperfiltration compared to Akita mice with a presumably intact TGF9
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