**5. Conclusion**

90 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

or chemical inhibition of collagen crosslinking. *pkd1a/b*- and *pkd2*-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of *pkd1a/b* also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with PI3 kinase inhibitors wortmannin or LY-29400 also exhibited dysregulation of *col2a1* expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. They suggested that *pkd1a/b* and *pkd2* interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.

Patricia Wilson and colleagues have recently implicated the role of focal adhesions in cystogenesis (Israeli et al., 2010). By comparing ARPKD cells, normal age matched human fetal (HFCT) cells and HFCT cells with 85% fibrocystin-1 silencing, they observed that fibrocystin-1-deficient cells had accelerated attachment and spreading on collagen matrix and decreased motility. Also, the fibrocystin-1-deficient cells were associated with longer paxillin-containing focal adhesions, more complex actin-cytoskeletal rearrangements, and

One of the features of PKD, particularly ADPKD is the high variability in the age of onset of renal functional decline and the severity of disease progression. This variability has been attributed to mutations in other disease modifier genes (second hit) as well as epigenetic factors. Even if ECM abnormalities fail to be the primary PKD defect, it is almost certain that they play an important role in disease progression by contributing to renal fibrosis. Although there is not much known about the contribution of renal fibrosis in PKD disease progression, a recent review by Jill Norman presents a comprehensive and convincing argument to focus on this area of investigation (Norman, 2011). In this review, it is pointed out that in ADPKD, expansion of cysts and loss of renal function are associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of chronic kidney disease (CKD), in ADPKD, fibrosis has been identified as the most significant manifestation associated with an increased rate of progression to ESRD. It is important to note that although fibrosis in CKD has been studied extensively, little is known about the mechanisms underlying PKD fibrosis. In this review, she concludes that the current data indicate that fibrosis associated with ADPKD shares at least some of the "classical" features of fibrosis in CKD (increased interstitial collagens, changes in MMPs, overexpression of TIMP-1, over-expression of PAI-1 and increased TGFβ) and points out that there are also some unique and stage-specific features. Based on the review of current literature, she suggests that epithelial changes appear to precede and to cause changes in the interstitium. It is also proposed that the development of fibrosis in ADPKD is a biphasic process with alterations in the cystic epithelia followed by changes in the interstitial fibroblasts and that reciprocal interaction between these cell types precipitate a progressive accumulation of ECM in the interstitial compartment. Since fibrosis is a major component of ADPKD it follows that preventing or slowing fibrosis should retard disease progression

increased levels of total 1-integrin, c-Src, and paxillin.

**4. ECM and PKD fibrosis** 

with obvious therapeutic benefits.

New studies cited in this review bring back the focus on the role ECM in PKD cystogenesis and fibrosis. Current results such as the study showing laminin alpha 5 hypomorphic mutation leads to cystic kidneys in mice, abnormal expression of laminin-332 in cysts and precystic tubules of PCK rat kidneys and aberrant expression of laminin-332 and integrin beta 4 in human ADPKD tissues, all point to the possible role of abnormal ECM in PKD cystogenesis. However it is possible that the mechanism that causes cyst formation is something other than the primary ECM defect and that the abnormal ECM observed in PKD aids in the progression of the disease by contributing to the mechanisms of fibrosis.
