Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria

Ruhul Amin, John Asplin, Daniel Jung, Mohamed Bashir, Altayeb Alshaikh, Sireesha Ratakonda, Sapna Sharma, Sohee Jeon, Ignacio Granja, Dietrich Matern, Hatim Hassan

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets.

Original languageEnglish (US)
JournalKidney International
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Hyperoxaluria
Intestinal Secretions
Oxalates
Obesity
Cytokines
Kidney Calculi
Inflammation
Hyperphagia
Calcium Oxalate
Messenger RNA
Body Size
Proteins
Urine

Keywords

  • Hyperoxaluria
  • Inflammation
  • Intestinal oxalate secretion
  • Obesity
  • SLC26A6

ASJC Scopus subject areas

  • Nephrology

Cite this

Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria. / Amin, Ruhul; Asplin, John; Jung, Daniel; Bashir, Mohamed; Alshaikh, Altayeb; Ratakonda, Sireesha; Sharma, Sapna; Jeon, Sohee; Granja, Ignacio; Matern, Dietrich; Hassan, Hatim.

In: Kidney International, 01.01.2018.

Research output: Contribution to journalArticle

Amin, R, Asplin, J, Jung, D, Bashir, M, Alshaikh, A, Ratakonda, S, Sharma, S, Jeon, S, Granja, I, Matern, D & Hassan, H 2018, 'Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria', Kidney International. https://doi.org/10.1016/j.kint.2017.11.011
Amin, Ruhul ; Asplin, John ; Jung, Daniel ; Bashir, Mohamed ; Alshaikh, Altayeb ; Ratakonda, Sireesha ; Sharma, Sapna ; Jeon, Sohee ; Granja, Ignacio ; Matern, Dietrich ; Hassan, Hatim. / Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria. In: Kidney International. 2018.
@article{59a75447687e413b8ae3b237b4919cc1,
title = "Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria",
abstract = "Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80{\%}) and total protein (- 62{\%}) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets.",
keywords = "Hyperoxaluria, Inflammation, Intestinal oxalate secretion, Obesity, SLC26A6",
author = "Ruhul Amin and John Asplin and Daniel Jung and Mohamed Bashir and Altayeb Alshaikh and Sireesha Ratakonda and Sapna Sharma and Sohee Jeon and Ignacio Granja and Dietrich Matern and Hatim Hassan",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.kint.2017.11.011",
language = "English (US)",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria

AU - Amin, Ruhul

AU - Asplin, John

AU - Jung, Daniel

AU - Bashir, Mohamed

AU - Alshaikh, Altayeb

AU - Ratakonda, Sireesha

AU - Sharma, Sapna

AU - Jeon, Sohee

AU - Granja, Ignacio

AU - Matern, Dietrich

AU - Hassan, Hatim

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets.

AB - Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets.

KW - Hyperoxaluria

KW - Inflammation

KW - Intestinal oxalate secretion

KW - Obesity

KW - SLC26A6

UR - http://www.scopus.com/inward/record.url?scp=85040967225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040967225&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2017.11.011

DO - 10.1016/j.kint.2017.11.011

M3 - Article

JO - Kidney International

JF - Kidney International

SN - 0085-2538

ER -