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01-09-2011 | Review

Calcium signaling triggered by ouabain protects the embryonic kidney from adverse developmental programming

Authors: Georgiy R. Khodus, Markus Kruusmägi, Juan Li, Xiao-Li Liu, Anita Aperia

Published in: Pediatric Nephrology | Issue 9/2011

Abstract

The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards formation of the kidney’s functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that the sodium-potassium-adenosine triphosphatase (Na, K-ATPase) ligand ouabain triggers, via the Na, K-ATPase/ inositol 1,4,5-trisphosphate receptor signalosome, a calcium-nuclear factor-kappa B (NF-κB) signal that protects kidney development from adverse effects of malnutrition. Serum deprivation resulted in severe retardation of nephron formation and robust increase in apoptotic rate, but in ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Depletion of intracellular calcium stores and inhibition of NF-κB activity abolished the rescuing effect of ouabain. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given low-protein diets and treated with ouabain or vehicle throughout pregnancy.

Ingelfinger JR (2004) Pathogenesis of perinatal programming. Curr Opin Nephrol Hypertens 13:459–464CrossRef

Luyckx VA, Brenner BM (2010) The clinical importance of nephron mass. J Am Soc Nephrol 21:898–910CrossRef

Schreuder M, Delemarre-van de Waal H, van Wijk A (2006) Consequences of intrauterine growth restriction for the kidney. Kidney Blood Press Res 29:108–125CrossRef

Woods LL, Weeks DA, Rasch R (2004) Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int 65:1339–1348CrossRef

Hughson M, Farris AB 3rd, Douglas-Denton R, Hoy WE, Bertram JF (2003) Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int 63:2113–2122CrossRef

Schreuder MF, Nyengaard JR, Fodor M, van Wijk JA, Delemarre-van de Waal HA (2005) Glomerular number and function are influenced by spontaneous and induced low birth weight in rats. J Am Soc Nephrol 16:2913–2919CrossRef

Welham SJ, Wade A, Woolf AS (2002) Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int 61:1231–1242CrossRef

Nijland MJ, Ford SP, Nathanielsz PW (2008) Prenatal origins of adult disease. Curr Opin Obstet Gynecol 20:132–138CrossRef

Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM (2008) Low birth weight increases risk for end-stage renal disease. J Am Soc Nephrol 19:151–157CrossRef

10.

Miyakawa-Naito A, Uhlen P, Lal M, Aizman O, Mikoshiba K, Brismar H, Zelenin S, Aperia A (2003) Cell signaling microdomain with Na, K-ATPase and inositol 1, 4, 5-trisphosphate receptor generates calcium oscillations. J Biol Chem 278:50355–50361CrossRef

11.

Zhang S, Malmersjo S, Li J, Ando H, Aizman O, Uhlen P, Mikoshiba K, Aperia A (2006) Distinct role of the N-terminal tail of the Na, K-ATPase catalytic subunit as a signal transducer. J Biol Chem 281:21954–21962CrossRef

12.

Aizman O, Uhlen P, Lal M, Brismar H, Aperia A (2001) Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc Natl Acad Sci USA 98:13420–13424CrossRef

13.

Aperia A (2007) New roles for an old enzyme: Na, K-ATPase emerges as an interesting drug target. J Intern Med 261:44–52CrossRef

14.

Berridge MJ (2007) Inositol trisphosphate and calcium oscillations. Biochem Soc Symp 74:1–7CrossRef

15.

Webb SE, Miller AL (2003) Calcium signalling during embryonic development. Nat Rev Mol Cell Biol 4:539–551CrossRef

16.

Li J, Zelenin S, Aperia A, Aizman O (2006) Low doses of ouabain protect from serum deprivation-triggered apoptosis and stimulate kidney cell proliferation via activation of NF-kappaB. J Am Soc Nephrol 17:1848–1857CrossRef

17.

Kobayashi D, Kobayashi M, Matsumoto K, Ogura T, Nakafuku M, Shimamura K (2002) Early subdivisions in the neural plate define distinct competence for inductive signals. Development 129:83–93PubMed

18.

Leder P (2004) The formins: connecting embryonic pattern formation and hypofertility in the mouse. Ann NY Acad Sci 1038:75–79CrossRef

19.

Dressler GR (2006) The cellular basis of kidney development. Annu Rev Cell Dev Biol 22:509–529CrossRef

20.

Li J, Khodus GR, Kruusmagi M, Kamali-Zare P, Liu XL, Eklof AC, Zelenin S, Brismar H, Aperia A (2010) Ouabain protects against adverse developmental programming of the kidney. Nat Commun. doi:https://doi.org/10.1038/ncomms1043

21.

Ferrandi M, Molinari I, Barassi P, Minotti E, Bianchi G, Ferrari P (2004) Organ hypertrophic signaling within caveolae membrane subdomains triggered by ouabain and antagonized by PST 2238. J Biol Chem 279:33306–33314CrossRef

Title: Calcium signaling triggered by ouabain protects the embryonic kidney from adverse developmental programming
Authors: Georgiy R. Khodus
Markus Kruusmägi
Juan Li
Xiao-Li Liu
Anita Aperia
Publication date: 01-09-2011
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 9/2011
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-011-1816-y

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Calcium signaling triggered by ouabain protects the embryonic kidney from adverse developmental programming

Abstract

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Springer Medicine

Abstract

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