Connecting tubule glomerular feedback mediates tubuloglomerular feedback resetting after unilateral nephrectomy

Abstract

Unilaterally nephrectomized rats (UNx) have higher glomerular capillary pressure (P) that can cause significant glomerular injury in the remnant kidney. P is controlled by the ratio of afferent (Af-Art) and efferent arteriole resistance. Af-Art resistance in turn is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa; and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel (ENaC). Resetting of TGF post-UNx can allow systemic pressure to be transmitted to the glomerulus and cause renal damage, but the mechanism behind this resetting is unclear. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that CTGF is increased after UNx and contributes to TGF resetting. To test this hypothesis, we performed UNx in Sprague-Dawley (8) rats. Twenty-four hours after surgery, we performed micropuncture of individual nephrons and measured stop-flow pressure (P). P is an indirect measurement of P. Maximal TGF response at 40 nl/min was 8.9 ± 1.24 mmHg in sham-UNx rats and 1.39 ± 1.02 mmHg in UNx rats, indicating TGF resetting after UNx. When CTGF was inhibited with the ENaC blocker benzamil (1 μM/l), the TGF response was 12.29 ± 2.01 mmHg in UNx rats and 13.03 ± 1.25 mmHg in sham-UNx rats, indicating restoration of the TGF responses in UNx. We conclude that enhanced CTGF contributes to TGF resetting after UNx.

Physiology and Pathophysiology of Compensatory Adaptations of a Solitary Functioning Kidney

“…SNGFR is influenced by various intrarenal mechanisms including glomerular capillary pressure, single nephron plasma flow, and tubuloglomerular feedback (TGF) ( Blantz and Pelayo, 1984 ). The rise in SNGFR and glomerular capillary pressure following reduction in kidney mass has been associated with a reduction in afferent arteriole resistance and a right-ward shift in TGF ( Müller-Suur et al, 1980 ; Salmond and Seney, 1991 ; Brown et al, 2011 ; Monu et al, 2018 ). It has been suggested that the right-ward shift results in blunting (resetting) of TGF where significantly higher fluid flow rates are required to cause a TGF mediated inhibition of SNGFR ( Salmond and Seney, 1991 ).…”

“…Thus, this resetting of TGF permits the increase in SNGFR and increase in glomerular capillary pressure in the remaining nephrons following nephron loss. In the rat, resetting of TGF 24 h after unilateral nephrectomy is mediated by enhanced connecting tubule glomerular feedback (a feedback system that influences afferent arteriole dilatation and is associated with epithelial sodium transporter; ENaC) ( Monu et al, 2018 ). This resetting of TGF also sustains the increase in glomerular capillary pressure observed following 5/6th and unilateral nephrectomy in the rat ( Salmond and Seney, 1991 ).…”

A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback

“…This compensation includes an increase in the single nephron GFR and subsequent glomerular and tubular hypertrophy. After UNx, TGF is reset, and CTGF is very active [29]. The inhibition of CTGF after UNx restored the TGF response.…”

“…These results indicate that at least part of the TGF resetting is due to the CTGF that modulates the TGF response. More dramatic TGF resetting is observed in the remnant kidney after unilateral nephrectomy (UNx) [29]. When renal parenchyma is reduced, the remnant nephron must compensate by increasing the amount of sodium and water excretion.…”

Tubule-vascular feedback in renal autoregulation

“…Thus, for the same amount of Na ϩ in the MD, the vasoconstriction response is much less. This phenomenon is called TGF resetting and occurs in physiological and pathophysiological conditions, including in response to growth (9), pregnancy (5), unilateral nephrectomy (Unx) (26,28), increased NaCl intake, increased fluid volume (10), etc. These situations represent states where high Na ϩ excretion is needed and inappropriately high TGF activity could lead to salt and water retention.…”