Role of renal crystal deposition in the progression of polycystic kidney disease

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Autosomal-dominant polycystic kidney disease (ADPKD) is a common and inherited disease with a frequency of 1:500 in world’s population. The disease progresses slowly to renal failure, typically in the 4-6th decades of life. For unknown reasons the rate of progression varies from patient to patient even within the same family suggesting that environmental factors may influence disease progression. Recent results from animal studies suggest that renal insults are required – in addition to the gene mutation – for renal cysts to develop. But rare forms of renal injury seem unlikely to trigger the constant disease progression in humans.Recent results of the Weimbs Laboratory suggest that a much more prevalent form of subclinical renal insult is the trigger of renal cyst formation that determines the rate of progression in ADPKD: microcrystals that are sporadically lodged in renal tubule lumens. They show that deposition of calcium oxalate (CaOx) crystals in renal tubules lead to rapid activation of the mTOR and Src/STAT3 signaling pathways, which are both strongly activated in ADPKD, too. Additionally, CaOx crystal deposition leads to rapid tubule diameter widening that can be blocked by mTOR inhibition. These results indicate that tubule dilation is a purposeful, and previously unrecognized, protective mechanism that facilitates crystal excretion. After crystal clearance, tubule diameters normalize within a week. However, in mice lacking PC1 – the protein affected in ADPKD – CaOx challenge leads to persistent tubule dilation that “overshoots” to cystic progression. This suggests that PC1 is required for a return to normal tubule diameters after insults. We hypothesize (1) that tubule dilation is an innate renal protective mechanism against tubular crystals and (2) that this mechanism acts as a trigger for tubule dilation leading to cyst formation in ADPKD. If correct - these findings immediately open a new and highly feasible avenue for therapeutic intervention because well-established treatments for recurring nephrolithiasis (dietary changes, increased water intake, citrate) should also be effective in slowing the progression of ADPKD.Using mouse and rat models of CaOx nephrolithiasis we will investigate tubule dilation and signaling pathway activation in response to crystal deposition and test whether citrate treatment prevents these effects (Aim 1). Using pharmacological inhibitors and genetic mouse models we will determine if tubule dilation is required for effective crystal clearance (Aim 2). Using conditional knockout mice for the ablation of cilia or PC1, we will investigate if tubule crystal deposition acts as a trigger for cystogenesis (Aim 3). Using a mosaic PC1-KO mouse model and a rat model of PKD we will determine if crystal burden modulates disease severity in PKD.