Editing Torres's "Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities" 2007

===Abstract===
*Now that we know more about the genetics of PKD and have animal models, we're making some progress in rational treatment.
*This paper will summarize where we are in these treatments and the biology behind the current treatment goals.

===Introduction===
*Autosomal dominant PKD (ADPKD):
**Has two loci: PKD1 and PKD2 which code for PC1 and PC2.
**PC1 sits on the primary cilia and signals to PC2 which is also membrane bound and is a Ca permeable channel.
*Autosomal recessive PKD (ARPKD):
**Has one loci: PKHD1 which codes for fibrocystin.
**Fibrocystin is also a membrane glycoprotein and may interact with PC1 and / or PC2 to help regulate Ca levels.
*ADPKD and ARPKD look alike in many ways, even if they are inherited differently.
**They are similar in their progression and cyst formation, though there are some differences like the cell population of cyst origin.
*Animal models show us that the disease may be an issue of PC1 thresholds not being met and that the threshold might be different for given tissues.
*As of publication in 2007, there was no treatment for PKD.

===Animal models of PKD===
*We have some models and they have helped elucidate some of the diease etiology.
*Our models aren't great however, because some are defective in genes not known to be part of the human disease and some form cysts that don't resemble human cysts in morphology or location.
*We have come up with some genetically modified mouse models that have genes knocked out that are orthologous to human disease genes (think Pkd1 and Pkd2).
**These aren't perfect however, because one has a variable phenotype and the other has a progression like ARPKD and not ADPKD.
**These are, however, our best models yet.

===PKD pathway===
*Read figure 2 caption.
**"Fig. 2 Diagram depicting the hypothetical downstream effects of disrupting the polycystin pathway. In response to mechanical stimulation of the primary cilium, the polycystin-1/2 complex mediates Ca2+ entry into the cell which triggers Ca2+-induced Ca2+ release from the endoplasmic reticulum (ER). Polycystin-2 is also an intracellular Ca2+ channel that is required for the normal pattern of [Ca2+]i responses to agonist stimulation of Gq-coupled receptors. Polycystin-2 physically interacts with TRPC1 and contributes to store operated Ca2+ channel (SOC) activity. The cellular content of cAMP is determined by the balance between activities of synthesizing adenylyl cyclases (AC) and catabolizing cAMP phosphodiesterases (PDE) that hydrolyse cAMP to biologically inactive noncyclic 5¢-AMP. AC6 is the predominant AC in collecting duct principal cells. AC6 is stimulated by the a-subunit of heteromeric G-proteins (Gas). It is inhibited by Gai and by Ca2+. PDE1 in collecting duct principal cells is activated by Ca2+/calmodulin at Ca2+ concentrations achieved in response to agonist stimulation. Under conditions of relative Ca2+ deprivation cAMP stimulates ERK signalling in a protein kinase A (PKA), Src, Ras, and B-Raf dependent manner. Increased expression, mislocalization and activation of ErbB receptors may also contribute to ERK activation. Phosphorylation of tuberin by ERK may result in dissociation of tuberin and hamartin and activation of Rheb and mTOR."

===Treatment trials in animal models===
*Gene therapy seems unlike to work because of the challenges of delivering the gene to only a certain tissue and because over expression of Pkd1 generates a cystic phenotype as much as does under expression.
*Antioxidant therapies have been considered on the assumption that somatic mutations are generating / affecting disease (and antioxidants should decrease somatic mutations).
*Low protein diets may help by reducing oxygen consumption for metabolism and thus decreasing the free radical concentration that can damage DNA.
**Other diets may help reduce other damaging agents like arachadonic acid.
*ACE inhibitors seem to have a protective effect and are already being used in many PKD patients to treat hyperlipidemia and hypertension.
*Because epithelial proliferation generates the cysts, anti-proliferative agents have been applied to some success in animal models.
*"EGFR tyrosine kinase inhibitors, mTOR inhibitors, vasopressin V2 receptor antagonists and octreotide are currently the therapies best supported by preclinical studies and more likely to enter clinical trials."

===Clinical trials===
*It is hard to use renal function as a metric in PKD treatment because there can be decades of normal function in spite of the fact that the kidneys are growing morphologically gross cysts and the disease is progressing.
*Furthermore, it is difficult to do clinical trials because early intervention would require long (as in decades) committments to return for study measurements and interventions.
*Because of these difficulties the NIH funded a radiological study to look for some marker of disease progression.
**This study showed that the kidneys hypertrophy in all PKD cases and that growth correlates to disease progression.
**The study suggests that kidney size be used as a marker for disease progression in any clinical trials.