Role of Mitofusin 2 in the Renal Stress Response

The role of mitofusin 2 (MFN2), a key regulator of mitochondrial morphology and function in the renal stress response is unknown. To assess its role, the MFN2 floxed gene was conditionally deleted in the kidney of mice (MFN2 cKO) by Pax2 promoter driven Cre expression (Pax2Cre). MFN2 cKO caused severe mitochondrial fragmentation in renal epithelial cells that are critical for normal kidney tubular function. However, despite a small (20%) decrease in nephron number, newborn cKO pups had organ or tubular function that did not differ from littermate Cre-negative pups. MFN2 deficiency in proximal tubule epithelial cells in primary culture induced mitochondrial fragmentation but did not significantly alter ATP turnover, maximal mitochondrial oxidative reserve capacity, or the low level of oxygen consumption during cyanide exposure. MFN2 deficiency also did not increase apoptosis of tubule epithelial cells under non-stress conditions. In contrast, metabolic stress caused by ATP depletion exacerbated mitochondrial outer membrane injury and increased apoptosis by 80% in MFN2 deficient vs. control cells. Despite similar stress-induced Bax 6A7 epitope exposure in MFN2 deficient and control cells, MFN2 deficiency significantly increased mitochondrial Bax accumulation and was associated with greater release of both apoptosis inducing factor and cytochrome c. In conclusion, MFN2 deficiency in the kidney causes mitochondrial fragmentation but does not affect kidney or tubular function during development or under non-stress conditions. However, MFN2 deficiency exacerbates renal epithelial cell injury by promoting Bax-mediated mitochondrial outer membrane injury and apoptosis

Intractable hyponatremia complicated by a reset osmostat: a case report

Abstract Background Hyponatremia associated with a low serum osmolality is a common and confounding electrolyte disorder. Correcting hyponatremia is also complicated, especially in the setting of chronic hyponatremia. Here, we provide a rational approach to accurately detecting and safely treating acute on chronic euvolemic hyponatremia in the setting of acute polydipsia with a chronic reset osmostat. Case presentation A 71-year-old hispanic gentleman with chronic hyponatremia presented with hiccups, polydipsia, and a serum sodium concentration of 120 mEq/L associated with diffuse weakness, inattentiveness, and suicidal ideation. Symptomatic euvolemic hyponatremia warranted hypertonic saline treatment in the acute phase and water restriction in the chronic phase. Both interventions resulted in improvement in symptoms and/or the serum sodium concentration, but to a serum sodium level that persistently remained below the normal range. Remarkably, the urine osmolality appropriately fell when the serum sodium concentration fell below 126 mEq/L. Also remarkable was the appropriate increase in urine osmolality when the serum sodium concentration exceeded 126 mEq/L. The preservation of both concentration and dilution, albeit at a lower-than-normal serum osmolality, shows that the osmostat regulating antidiuretic hormone release had been “reset.” Both physiologic and pharmacologic resetting of the osmostat are discussed. Conclusions Preservation of urinary concentrating and diluting ability at a lower-than-normal serum sodium concentration, especially in the setting of chronic hyponatremia, is diagnostic of a reset osmostat. The presence of a reset osmostat often confounds the treatment of concomitant acute hyponatremia. Early recognition of a reset osmostat avoids the need to normalize serum sodium concentration, expedites hospital discharge, and limits potential harm from overcorrecting acute hyponatremia

β-Catenin Promotes Survival of Renal Epithelial Cells by Inhibiting Bax

Ischemia activates Bax, a proapoptotic BCL2 protein, as well as the prosurvival β-catenin/Wnt signaling pathway. To test the hypothesis that β-catenin/Wnt signaling regulates Bax-mediated apoptosis after induction of metabolic stress, which occurs during renal ischemia, we infected immortalized and primary proximal tubular epithelial cells with adenovirus to express either constitutively active or dominant negative β-catenin constructs. Constitutively active β-catenin significantly decreased apoptosis and improved cell survival after metabolic stress. Furthermore, active β-catenin decreased Bax activation, oligomerization, and translocation to mitochondria, and reduced both organelle membrane injury and apoptosis. Dominant negative β-catenin had the opposite effects. Because Akt regulates Bax, we examined the effects of the β-catenin mutants on Akt expression and activation. Constitutively active β-catenin increased Akt-1 expression and activation before and after stress, and treatment with a phosphatidylinositol-3 kinase inhibitor antagonized the protective effects of β-catenin on Akt activation, Bax inhibition, and cell survival. In addition, β-catenin significantly increased the rate of phosphorylation at Bax serine184, an Akt-specific target. Taken together, these results suggest that β-catenin/Wnt signaling promotes survival of renal epithelial cells after metabolic stress, in part by inhibiting Bax in a phosphatidylinositol-3 kinase/Akt-dependent manner