Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption
Scott C. Thomson, … , Dingjiu Bao, Roland C. Blantz
Scott C. Thomson, … , Dingjiu Bao, Roland C. Blantz
Published October 15, 1999
Citation Information: J Clin Invest. 1999;104(8):1149-1158. https://doi.org/10.1172/JCI5156.
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Article

Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption

Abstract

Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron GFR (SNGFR) to compensate for changes in late proximal flow (VLP). TGF responds within seconds and reacts over a narrow range of VLP that surrounds normal VLP. To accommodate sustained increases in VLP, TGF must reset around the new flow. We studied TGF resetting by inhibiting proximal reabsorption with benzolamide (BNZ; administered repeatedly over a 24-hour period) in Wistar-Froemter rats. BNZ acutely activates TGF, thereby reducing SNGFR. Micropuncture was performed 6–10 hours after the fourth BNZ dose, when diuresis had subsided. BNZ caused glomerular hyperfiltration, which was prevented with inhibitors of macula densa nitric oxide synthase (NOS). Because of hyperfiltration, BNZ increased VLP and distal flow, but did not affect the basal TGF stimulus (early distal salt concentration). BNZ slightly blunted normalized maximum TGF response and the basal state of TGF activation. BNZ sensitized SNGFR to reduction by S-methyl-thiocitrulline (SMTC) and caused the maximum TGF response to be strengthened by SMTC. Sensitization to type I NOS (NOS-I) blockers correlated with increased macula densa NOS-I immunoreactivity. Tubular transport measurements confirmed that BNZ affected TGF within the juxtaglomerular apparatus. During reduced proximal reabsorption, TGF resets to accommodate increased flow and SNGFR through a mechanism involving macula densa NOS.

Authors

Scott C. Thomson, Sebastian Bachmann, Magdalena Bostanjoglo, Carolyn A. Ecelbarger, Orjan W. Peterson, Doron Schwartz, Dingjiu Bao, Roland C. Blantz

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Figure 3

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Macula densa NOS and TGF resetting. (a) Proximal SNGFR during microperfu...
Macula densa NOS and TGF resetting. (a) Proximal SNGFR during microperfusion of the loop of Henle at 38 nL/min (maximum TGF) and 8 nL/min (minimum TGF, allowing for continued delivery of drug to the macula densa). Perfusion was with ATF or ATF + SMTC. The horizontal axis is arranged according to the chronology of the perfusion protocol. VP = microperfusion rate. Data shown are mean ± SEM for control (n = 16) and 6–10 hours post-BNZ nephrons (n = 15). When perfused with ATF, previous exposure to BNZ increased SNGFR, regardless of the state of TGF stimulation (P = 0.002). SMTC reduced SNGFR at either perfusion rate in both groups (P = 6 × 10–8 for the effect of SMTC within subjects across both groups). The influence of SMTC was enhanced by BNZ, such that SMTC reduced the differences between BNZ and control (P = 0.02 for the cross-term; group × SMTC with SNGFR averaged over both perfusion rates as dependent variable in ANOVA). (b) Increment in SNGFR that occurred when TGF was removed by reducing microperfusion from 38 nL/min to 8 nL/min. Values were normalized to SNGFR averaged between the 2 measurements. *P = 0.08 vs. BNZ-ATF. No other comparison approached significance. (c) Macula densa NOS-I immunoreactivity. **P < 0.05 vs. control.