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

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.

Ouabain Increases Gap Junctional Communication in Epithelial Cells

“…In rats that are exposed to malnutrition and serum-starved kidney explants, ouabain activates the signaling of the calcium-dependent transcription factor NF-κB, which protects kidney development from the adverse effects of malnutrition [39,40]. It is conceivable that if cytosolic Ca 2+ oscillatory waves diffuse across gap junctions, the enhancement of GJC by ouabain described in the present study may aid in the prevention of adverse events during kidney development.…”

Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections

“…Consequently, inhibition of calcium binding by a phenothiazine inhibits calcium signalling processes and therefore the processes of post-phagocytosis should be affected. Calcium signalling pathways of eukaryotic cells are affected by inhibitors of calcium transport [41][42][43][44][45][46][47][48][49]. As would be expected, phenothiazines are potent inhibitors of calcium transport [50].…”

How the Kidney Is Impacted by the Perinatal Maternal Environment to Develop Hypertension1

“…Although not completely understood, sex differences in gene expression in human and murine kidneys under baseline and disease conditions [61], if they could be further elucidated, could be utilized as preventative targets for sex-specific treatment of cardiovascular and renal disease. Besides RAS compromise, oligonephronia in undernourished rats is also attributed to apoptosis [62,63]. Undernutrition in the sheep also compromises nephron number [64].…”