Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies

Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways

Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption

To prevent dehydration, terrestrial animals and humans have developed a sensitive and versatile system to maintain their water homeostasis. In states of hypernatremia or hypovolemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary and binds its type-2 receptor in renal principal cells. This triggers an intracellular cAMP signaling cascade, which phosphorylates aquaporin-2 (AQP2) and targets the channel to the apical plasma membrane. Driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels. When water homeostasis is restored, AVP levels decline, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again. The action of AVP is counterbalanced by several hormones like prostaglandin E2, bradykinin, dopamine, endothelin-1, acetylcholine, epidermal growth factor, and purines. Moreover, AQP2 is strongly involved in the pathophysiology of disorders characterized by renal concentrating defects, as well as conditions associated with severe water retention. This review focuses on our recent increase in understanding of the molecular mechanisms underlying AVP-regulated renal water transport in both health and disease

Speculative Memory Checkpointing

High-frequency memory checkpointing is an important tech-nique in several application domains, such as automatic error recovery (where frequent checkpoints allow the sys-tem to transparently mask failures) and application debug-ging (where frequent checkpoints enable fast and accurate time-traveling support). Unfortunately, existing (typically incremental) checkpointing frameworks incur substantial per-formance overhead in high-frequency memory checkpointing applications, thus discouraging their adoption in practice. This paper presents Speculative Memory Checkpointing (SMC), a new low-overhead technique for high-frequency memory checkpointing. Our motivating analysis identifies key bottlenecks in existing frameworks and demonstrates that the performance of traditional incremental checkpoint-ing strategies in high-frequency checkpointing scenarios is not optimal. To fill the gap, SMC relies on working set estimation algorithms to eagerly checkpoint the memory pages that belong to the writable working set of the run-ning program and only lazily checkpoint the memory pages that do not. Our experimental results demonstrate that SMC is effective in reducing the performance overhead of prior solutions, is robust to variations in the workload, and incurs modest memory overhead compared to traditional incremental checkpointing