Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis: Implications for oxygen diffusion

Sarah E. Gazzard; Luise A. Cullen-McEwen; Marina Nikulina; Arnold B. Clever; Bruce S. Gardiner; David W. Smith; Chang Joon Lee; Jens R. Nyengaard; Roger G. Evans; John F. Bertram

doi:10.1002/ar.25576

Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis: Implications for oxygen diffusion

Sarah E. Gazzard, Luise A. Cullen-McEwen, Marina Nikulina, Arnold B. Clever, Bruce S. Gardiner, David W. Smith, Chang Joon Lee, Jens R. Nyengaard, Roger G. Evans, John F. Bertram^*

^*Corresponding author for this work

Department of Clinical Medicine - Core Centre for Molecular Morphology, Section for Stereology and Microscopy

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 μm²/μm³). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia.

Original language	English
Journal	Anatomical Record
Volume	308
Issue	5
Pages (from-to)	1492-1503
Number of pages	12
ISSN	1932-8486
DOIs	https://doi.org/10.1002/ar.25576
Publication status	Published - May 2025

Keywords

adenine
capillary
kidney
kidney interstitial fibrosis
oxygen diffusion

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10.1002/ar.25576

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@article{0682348a5bbf4ba382747d17243f8540,

title = "Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis: Implications for oxygen diffusion",

abstract = "Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 μm2/μm3). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia.",

keywords = "adenine, capillary, kidney, kidney interstitial fibrosis, oxygen diffusion",

author = "Gazzard, {Sarah E.} and Cullen-McEwen, {Luise A.} and Marina Nikulina and Clever, {Arnold B.} and Gardiner, {Bruce S.} and Smith, {David W.} and Lee, {Chang Joon} and Nyengaard, {Jens R.} and Evans, {Roger G.} and Bertram, {John F.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.",

year = "2025",

month = may,

doi = "10.1002/ar.25576",

language = "English",

volume = "308",

pages = "1492--1503",

journal = "Anatomical Record",

issn = "1932-8486",

publisher = "John Wiley & Sons Inc.",

number = "5",

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Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis: Implications for oxygen diffusion. / Gazzard, Sarah E.; Cullen-McEwen, Luise A.; Nikulina, Marina et al.
In: Anatomical Record, Vol. 308, No. 5, 05.2025, p. 1492-1503.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis

T2 - Implications for oxygen diffusion

AU - Gazzard, Sarah E.

AU - Cullen-McEwen, Luise A.

AU - Nikulina, Marina

AU - Clever, Arnold B.

AU - Gardiner, Bruce S.

AU - Smith, David W.

AU - Lee, Chang Joon

AU - Nyengaard, Jens R.

AU - Evans, Roger G.

AU - Bertram, John F.

PY - 2025/5

Y1 - 2025/5

N2 - Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 μm2/μm3). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia.

AB - Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 μm2/μm3). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia.

KW - adenine

KW - capillary

KW - kidney

KW - kidney interstitial fibrosis

KW - oxygen diffusion

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U2 - 10.1002/ar.25576

DO - 10.1002/ar.25576

M3 - Journal article

C2 - 39238265

AN - SCOPUS:85203255944

SN - 1932-8486

VL - 308

SP - 1492

EP - 1503

JO - Anatomical Record

JF - Anatomical Record

IS - 5

ER -

Alterations to peritubular capillary structure in a rat model of kidney interstitial fibrosis: Implications for oxygen diffusion

Abstract

Keywords

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