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Macroautophagy is a ubiquitous mechanism for the bulk removal of macromolecules and cell organelles from the cell. Periyasamy-Thandavan and colleagues report that cisplatin activates autophagy in renal tubular cells and that autophagy plays a role in decreasing apoptosis of tubular cells induced by cisplatin. This finding provides novel evidence that autophagy may play a role in ameliorating the effects of acute injury on the kidney.

Background The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells. Methods Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the α1 or the α2 isoform of the catalytic domain of AMPK. MPT cells were subjected to ATP depletion using antimycin A. Results Surprisingly, there was no difference in the amount of death induced by metabolic stress of MPT cells from either type of AMPK KO mice compared to its WT control. Moreover, inhibition of the activity of the α1 isoform in primary MPT cells from α2 -/- mice (pharmacologically, via compound C) or inhibition of the α2 isoform in primary MPT cells from α1 -/- mice (molecularly, via knockdown) both decreased cell viability equivalently in response to metabolic stress. The explanation for this unexpected result appears to be an adaptive increase in expression of the non-deleted α-isoform. As a consequence, total α-domain expression (i.e. α1 + α2), is comparable in kidney cortex and in cultured MPT cells derived from either type of KO mouse versus its WT control. Importantly, each α-isoform appears able to compensate fully for the absence of the other, with respect to both the phosphorylation of downstream targets of AMPK and the amelioration of stress-induced cell death. Conclusions These findings not only confirm the importance of AMPK as a pro-survival kinase in MPT cells during metabolic stress, but also show, for the first time, that each of the two α-isoforms can substitute for the other in MPT cells from AMPK KO mice with regard to amelioration of stress-induced loss of cell viability.

BACKGROUND: The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells. METHODS: Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the alpha1 or the alpha2 isoform of the catalytic domain of AMPK. MPT cells were subjected to ATP depletion using antimycin A. RESULTS: Surprisingly, there was no difference in the amount of death induced by metabolic stress of MPT cells from either type of AMPK KO mice compared to its WT control. Moreover, inhibition of the activity of the alpha1 isoform in primary MPT cells from alpha2-/- mice (pharmacologically, via compound C) or inhibition of the alpha2 isoform in primary MPT cells from alpha1-/- mice (molecularly, via knockdown) both decreased cell viability equivalently in response to metabolic stress. The explanation for this unexpected result appears to be an adaptive increase in expression of the non-deleted alphaisoform. As a consequence, total As a consequence-domain expression (i.e. alpha1 + alpha2), is comparable in kidney cortex and in cultured MPT cells derived from either type of KO mouse versus its WT control. Importantly, each alphaisoform appears able to compensate fully for the absence of the other, with respect to both the phosphorylation of downstream targets of AMPK and the amelioration of stress-induced cell death. CONCLUSIONS: These findings not only confirm the importance of AMPK as a pro-survival kinase in MPT cells during metabolic stress, but also show, for the first time, that each of the two alpha-isoforms can substitute for the other in MPT cells from AMPK KO mice with regard to amelioration of stress-induced loss of cell viability.

The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells. Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the [alpha]1 or the [alpha]2 isoform of the catalytic domain of AMPK. MPT cells were subjected to ATP depletion using antimycin A. Surprisingly, there was no difference in the amount of death induced by metabolic stress of MPT cells from either type of AMPK KO mice compared to its WT control. Moreover, inhibition of the activity of the [alpha]1 isoform in primary MPT cells from [alpha]2.sup.-/- mice (pharmacologically, via compound C) or inhibition of the [alpha]2 isoform in primary MPT cells from [alpha]1.sup.-/- mice (molecularly, via knockdown) both decreased cell viability equivalently in response to metabolic stress. The explanation for this unexpected result appears to be an adaptive increase in expression of the non-deleted [alpha]-isoform. As a consequence, total [alpha]-domain expression (i.e. [alpha]1 + [alpha]2), is comparable in kidney cortex and in cultured MPT cells derived from either type of KO mouse versus its WT control. Importantly, each [alpha]-isoform appears able to compensate fully for the absence of the other, with respect to both the phosphorylation of downstream targets of AMPK and the amelioration of stress-induced cell death. These findings not only confirm the importance of AMPK as a pro-survival kinase in MPT cells during metabolic stress, but also show, for the first time, that each of the two [alpha]-isoforms can substitute for the other in MPT cells from AMPK KO mice with regard to amelioration of stress-induced loss of cell viability.

The systemic and renal hemodynamic responses to nitric oxide (NO) inhibition with L-Name were compared in both normotensive, normovolemic rats and in rats following acute hemorrhagic hypotension. The mean arterial blood pressure increased in normovolemic as well as in hemorrhaged, hypotensive rats. The systemic vascular resistance also increased in both groups, but the increase was greater in normotensive rats (104 ± 11%) than in hypotensive rats (64 ± 14%). The renal vascular resistance also increased more in normotensive rats (189 ± 20%) than in hypotensive rats (102 ± 19%; p < 0.05). The glomerular filtration rate was markedly reduced by L-Name in normovolemic rats (from 3.0 ± 0.1 to 2.1 ± 0.1 ml/min/300 g), but increased in hemorrhaged rats following L-Name (from 1.8 ± 0.2 to 2.5 ± 0.2 ml/min/300 g). In summary, the L-Name-induced increase in vascular resistance is markedly reduced following hemorrhage, suggesting that NO production or availability is reduced. However, the NO production continues in the hemorrhaged rat and contributes substantially to the hypotension and functional renal insufficiency associated with acute severe volume depletion.