Urinary exosomes in the diagnosis of Gitelman and Bartter syndromes

Corbetta, Samuele; Raimondo, Francesca; Tedeschi, Silvana; Syrén, Marie Louise; Rebora, Paola; Savoia, Andrea; Baldi, Lorenza; Bettinelli, Alberto; Pitto, Marina

doi:10.1093/ndt/gfu362

Cited by 54 publications

(61 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In humans, urinary extracellular vesicles (uEVs), including exosomes, have been extensively characterized and studied as non-invasive biomarkers for renal tubular disorders [25–28]. uEVs are nanosized membranous vesicles released from all cells lining the nephron.…”

Section: Introductionmentioning

confidence: 99%

NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity

et al. 2017

View full text Add to dashboard Cite

Animal studies have shown that the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus can activate the thiazide-sensitive NaCl cotransporter (NCC). A common side effect of CNIs is hypertension. Renal salt transporters such as NCC are excreted in urinary extracellular vesicles (uEVs) after internalization into multivesicular bodies. Human studies indicate that CNIs also increase NCC abundance in uEVs, but results are conflicting and no relationship with NCC function has been shown. Therefore, we investigated the effects of CsA and Tac on the abundance of both total NCC (tNCC) and phosphorylated NCC at Thr60 phosphorylation site (pNCC) in uEVs, and assessed whether NCC abundance in uEVs predicts the blood pressure response to thiazide diuretics. Our results show that in kidney transplant recipients treated with cyclosporine (n = 9) or tacrolimus (n = 23), the abundance of both tNCC and pNCC in uEVs is 4–5 fold higher than in CNI-free kidney transplant recipients (n = 13) or healthy volunteers (n = 6). In hypertensive kidney transplant recipients, higher abundances of tNCC and pNCC prior to treatment with thiazides predicted the blood pressure response to thiazides. During thiazide treatment, the abundance of pNCC in uEVs increased in responders (n = 10), but markedly decreased in non-responders (n = 8). Thus, our results show that CNIs increase the abundance of both tNCC and pNCC in uEVs, and these increases correlate with the blood pressure response to thiazides. This implies that assessment of NCC in uEVs could represent an alternate method to guide anti-hypertensive therapy in kidney transplant recipients.

show abstract

Section: Introductionmentioning

confidence: 99%

NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The cargo of uEVs reflects changes in the expression of different proteins present in the epithelial cells of the nephron, including the total and phosphorylated forms of NCC [20,67,68]. Indeed, it has been demonstrated that patients with Gitelman syndrome display a decreased NCC abundance in uEVs [67,69]. On the other hand, patients with Gordon syndrome show higher levels of NCC in the kidney and this increased abundance was also observed in the uEVs [68].…”

Section: The Role Of Nccsv In (Patho)physiologymentioning

confidence: 99%

Role of the alternative splice variant of NCC in blood pressure control

2018

View full text Add to dashboard Cite

The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC3) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCCSV), in several (patho)physiological conditions. In the human kidney, NCCSV localizes to the apical membrane of the DCT and could constitute a functional route for renal sodium-chloride reabsorption. Analysis of urinary extracellular vesicles (uEVs), a non-invasive method for measuring renal responses, demonstrated that NCCSV abundance changes in response to acute water loading and correlates with patients’ thiazide responsiveness. Furthermore, a novel phosphorylation site at serine 811 (S811), exclusively present in NCCSV, was shown to play an instrumental role in NCCSV as well as NCC3 function. This review aims to summarize these new insights of NCCSV function in humans that broadens the understanding on NCC regulation in blood pressure control.

show abstract

“…Other groups have used exosome analysis to quantify NCC expression in response to high and low salt diets [217], and in limited fashion pNCC in patients with primary aldosteronism [216]. A recent study looked at NCC and NKCC2 expression in patients with Gitelman and Bartter syndrome [228]. The investigators found very low or undetectable NCC in exosomes of patients with Gitelman syndrome and similarly low levels of NKCC2 in patients with Bartter syndrome as compared with control subjects.…”

Section: What Are Urinary Exosomes and How Do We Isolate Them?mentioning

confidence: 99%

“…Mayan et al loaded western blot samples with a quantity of protein representing an amount of urine containing 3mg of creatinine [187]. Corbetta et al used standard amounts of protein on their gels, but expressed density per mg of creatinine to standardise [228]. Esteva-Font et al normalised human samples to creatinine and animal samples to time in one study [217], as did the study by van der Lubbe et al [216].…”

Section: Normalisation Of Samplesmentioning

confidence: 99%