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Zsengeller, Zsuzsanna

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Zsengeller

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Zsuzsanna

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Zsengeller, Zsuzsanna
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    Loss of kAE1 expression in collecting ducts of end-stage kidneys from a family with SLC4A1 G609R-associated distal renal tubular acidosis
    (Oxford University Press, 2016) Vichot, Alfred A.; Zsengeller, Zsuzsanna; Shmukler, Boris; Adams, Nancy D.; Dahl, Neera K.; Alper, Seth
    Distal renal tubular acidosis caused by missense mutations in kidney isoform of anion exchanger 1 (kAE1/SLC4A1), the basolateral membrane Cl−/HCO3− exchanger of renal alpha-intercalated cells, has been extensively investigated in heterologous expression systems but rarely in human kidneys. The preferential apical localization of distal renal tubular acidosis (dRTA)-associated kAE1 mutants R901X, G609R and M909T in cultured epithelial monolayers has not been examined in human kidney. Here, we present kidney tissues from dRTA-affected siblings heterozygous for kAE1 G609R, characterized by predominant absence rather than mistargeting of kAE1 in intercalated cells. Thus, studies of heterologous recombinant expression of mutant proteins should be, whenever possible, interpreted in comparison to affected patient tissues.
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    Congenital chloride-losing diarrhea in a Mexican child with the novel homozygous SLC26A3 mutation G393W
    (Frontiers Media S.A., 2015) Reimold, Fabian Raoul; Balasubramanian, Savithri; Doroquez, David B.; Shmukler, Boris; Zsengeller, Zsuzsanna; Saslowsky, David E.; Thiagarajah, Jay; Stillman, Isaac; Lencer, Wayne; Wu, Bai-Lin; Villalpando-Carrion, Salvador; Alper, Seth
    Congenital chloride diarrhea is an autosomal recessive disease caused by mutations in the intestinal lumenal membrane Cl−/HCO−3 exchanger, SLC26A3. We report here the novel SLC26A3 mutation G393W in a Mexican child, the first such report in a patient from Central America. SLC26A3 G393W expression in Xenopus oocytes exhibits a mild hypomorphic phenotype, with normal surface expression and moderately reduced anion transport function. However, expression of HA-SLC26A3 in HEK-293 cells reveals intracellular retention and greatly decreased steady-state levels of the mutant polypeptide, in contrast to peripheral membrane expression of the wildtype protein. Whereas wildtype HA-SLC26A3 is apically localized in polarized monolayers of filter-grown MDCK cells and Caco2 cells, mutant HA-SLC26A3 G393W exhibits decreased total polypeptide abundance, with reduced or absent surface expression and sparse punctate (or absent) intracellular distribution. The WT protein is similarly localized in LLC-PK1 cells, but the mutant fails to accumulate to detectable levels. We conclude that the chloride-losing diarrhea phenotype associated with homozygous expression of SLC26A3 G393W likely reflects lack of apical surface expression in enterocytes, secondary to combined abnormalities in polypeptide trafficking and stability. Future progress in development of general or target-specific folding chaperonins and correctors may hold promise for pharmacological rescue of this and similar genetic defects in membrane protein targeting.
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    PGC1α-dependent NAD biosynthesis links oxidative metabolism to renal protection
    (2016) Tran, Mei T.; Zsengeller, Zsuzsanna; Berg, Anders; Khankin, Eliyahu; Bhasin, Manoj; Kim, Wondong; Clish, Clary B.; Stillman, Isaac; Karumanchi, Subbian; Rhee, Eugene; Parikh, Samir
    The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischemia. Indeed, acute kidney injury (AKI) affects 3% of all hospitalized patients.1,2 Here we show that the mitochondrial biogenesis regulator, PGC1α,3,4 is a pivotal determinant of renal recovery from injury by regulating NAD biosynthesis. Following renal ischemia, PGC1α−/− mice developed local deficiency of the NAD precursor niacinamide (Nam), marked fat accumulation, and failure to re-establish normal function. Remarkably, exogenous Nam improved local NAD levels, fat accumulation, and renal function in post-ischemic PGC1α−/− mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulated the effects of Nam supplementation, including more local NAD and less fat accumulation with better renal function after ischemia. PGC1α coordinately upregulated the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuated the de novo pathway. Nam enhanced NAD via the enzyme NAMPT and augmented production of the fat breakdown product beta-hydroxybutyrate (β-OHB), leading to increased prostaglandin PGE2, a secreted autocoid that maintains renal function.5 Nam treatment reversed established ischemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of β-OHB signaling or prostaglandins similarly abolished PGC1α-dependent renoprotection. Given the importance of mitochondrial health in aging and the function of metabolically active organs, the results implicate Nam and NAD as key effectors for achieving PGC1α-dependent stress resistance.