Tamm-Horsfall protein-mRNA synthesis is localized to the thick ascending limb of Henle's loop in rat kidney

Bachmann, S.; Metzger, Rainer; Bunnemann, Bernd

doi:10.1007/bf00272616

Cited by 111 publications

(78 citation statements)

References 19 publications

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“…An 8.5-fold reduction of UMOD in Ddah1 PT2/2 suggests that functional changes in MAMEs and NO synthesis within the proximal tubule are communicated downstream along the nephron to the thick ascending limb, where UMOD is exclusively expressed. 41 A link between NO activity and UMOD expression was confirmed in wild-type mice exposed to a nonselective NOS inhibitor (L-NAME), which resulted in reduced UMOD protein expression in kidney tissue and urine. Of note, NO exerts regulatory control over two transcription factors-nuclear factor of activated T cells 42 and Oct-1 43 -both of which have consensus-binding sites in the promoter region of UMOD.…”

Section: Discussionmentioning

confidence: 92%

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

Tomlinson

Caplin

Boruc

et al. 2015

Journal of the American Society of Nephrology

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Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylargininemetabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1 PT2/2 mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylargininemetabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulinrelated mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function.

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Section: Discussionmentioning

confidence: 92%

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

Tomlinson

Caplin

Boruc

et al. 2015

Journal of the American Society of Nephrology

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“…18,19 Aviv et al 20,21 reviewed previously reported clinical studies that indicated that the thick ascending limb (TAL) had a pivotal role in the susceptibility of Blacks to HTN. A mechanism was proposed in which an increase in NKCC2 activity could lead to the expansion of the extracellular volume and thus be associated with HTN.…”

Section: Discussionmentioning

confidence: 99%

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

et al. 2012

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Hypertension is an important risk factor for chronic kidney disease. The kidney, in turn, has an important role in the regulation of blood pressure (BP). On the basis of a genome-wide association study, single-nucleotide polymorphisms in the uromodulin (UMOD) promoter region had been considered to influence both renal sodium reabsorption and BP. In this study, we asked whether common variants across the UMOD gene influence BP in a community-based Chinese cohort. We screened seven common variants across the UMOD locus in a community-based population from Beijing, including 1000 individuals with 48% males and an average age of 63.7 ± 9.0 years. The urinary UMOD concentration was measured by enzyme-linked immunosorbent assay. We then analyzed the association of common variants of UMOD with BP. The UMOD promoter common variant rs13333226 G/A is associated with diastolic BP (DBP), and G allele carriers have higher DBP compared with A/A homozygotes (P ¼ 0.035). The variant rs6497476 C/T predicted the DBP level, with C homozygotes having a higher DBP compared with CT heterozygotes and T homozygotes (P ¼ 0.025). Urinary UMOD excretion was correlated with urinary sodium excretion (R ¼ 0.239, P ¼ 0.656*10 À13 ). We determined that common variants of UMOD are associated with DBP level in a community-based Chinese cohort.

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“…9 TGF should not be affected in the HSV1-tk model because injury is limited to the TAL and spares the macula densa 22 ; however, to demonstrate conclusively that TGF activation is a major contributory factor would require tubular microperfusion studies. The presence of luminal casts suggests that tubular backleak from obstruction also contributes to AKI.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis of the Thick Ascending Limb Results in Acute Kidney Injury

Srichai¹,

Hao²,

Davis³

et al. 2008

Journal of the American Society of Nephrology

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Ischemia-or toxin-induced acute kidney injury is generally thought to affect the cells of the proximal tubule, but it has been difficult to define the involvement of other tubular segments because of the widespread damage caused by ischemia/reperfusion or toxin-induced injury in experimental models. For evaluation of whether thick ascending limb (TAL)-specific epithelial injury results in acute kidney injury, a novel transgenic mouse model that expresses the herpes simplex virus 1 thymidine kinase gene under the direction of the TAL-specific Tamm-Horsfall protein promoter was generated. After administration of gancyclovir, these mice demonstrated apoptosis only in TAL cells, with little evidence of neutrophil infiltration. Compared with control mice, blood urea nitrogen and creatinine levels were at least five-fold higher in the transgenic mice, which also developed oliguria and impaired urinary concentrating ability. These findings suggest that acute injury targeted only to the TAL is sufficient to cause severe acute kidney injury in mice with features similar to those observed in humans. 19: 153819: -154619: , 200819: . doi: 10.1681 Acute kidney injury (AKI), which contributes significantly to morbidity and mortality among hospitalized patients, 1 is frequently multifactorial, 2 with ischemia and nephrotoxins being the most common causes. Regardless of cause, histologic findings include dilated and flattened epithelium, loss of tubular epithelial cells, and the presence of TammHorsfall protein (THP)-rich casts. Frank necrosis is not usually apparent, and apoptotic cells are consistently found in both ischemic and nephrotoxic forms of clinical AKI. 3,4 At the cellular level, actin cytoskeletal abnormalities lead to loss of cell polarity and relocation of cell adhesion molecules. 5,6 Endothelial dysfunction and inflammation are present, although morphologic changes are subtle. 7,8 A key unanswered question in AKI is how the kidney protects itself from devastating losses of body fluids as a result of the failure of glomerular ultrafiltrate reabsorption. One proposed mechanism is tubuloglomerular feedback (TGF), whereby increased distal delivery of solutes to the macula densa results in feedback signals to the glomerulus to decrease GFR by afferent arteriole constriction. After injury, tubular epithelial cell reabsorption of sodium is impaired, which results in increased distal delivery of NaCl and subsequent activation of TGF. The decreased renal blood flow and GFR result in oliguria and, in severe cases, anuria. This J Am Soc Nephrol

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Tamm-Horsfall protein-mRNA synthesis is localized to the thick ascending limb of Henle's loop in rat kidney

Cited by 111 publications

References 19 publications

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

Apoptosis of the Thick Ascending Limb Results in Acute Kidney Injury

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