UC Santa Barbara
Microcrystals promote cystogenesis and exacerbate autosomal dominant polycystic kidney disease
- Author(s): Torres, Jacob Alexander
- Advisor(s): Weimbs, Thomas
- et al.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder affecting approximately 2.5 million people worldwide. It is the number one, life-threatening monogenic disorder known, caused by mutations in either the Pkd1 or Pkd2 genes resulting in numerous fluid-filled cysts within the kidneys. ADPKD presents in the 2nd decade of life and presents with progressive renal decline and eventually to end stage renal disease (ESRD) in the 5th to 6th decade of life for half of all patients. Currently no treatments exist to ameliorate or cure ADPKD, creating a large financial burden on both the health care system, the patient, and their care-givers. Treatment options once patients reach ESRD are limited to dialysis and kidney transplant. Since the discovery of the genetic link to ADPKD, there has been intense research to understand what role the Pkd1/2 genes play in the formation of cysts and the progression of ADPKD. The slow progression of ADPKD and the difference in disease severity between individuals implies that there may be environmental factors acting as causative agents in promoting cyst formation. Animal models of ADPKD appear to be more susceptible to cyst formation following injury with nephrotoxic chemicals, ischemia, and partial or total unilateral nephrectomy. These data demonstrate that the injured state is a driver of cyst formation once Pkd1/2 have been mutated, but these experimental approaches are not representative of normal environmental injuries to the kidney. The focus of my research is to elucidate an environmental agent that can promote cystogenesis in an otherwise healthy individual. The kidney is responsible for filtering solutes from the blood which include ions and molecules that under the right circumstances can form precipitates in the urinary filtrate. It is our hypothesis that the endogenous kidney injury in ADPKD patients results via the precipitation of microcrystals and the inappropriate response to crystal clearance. The kidney is producing sub-clinical microcrystals daily that are excreted into the urine without incident. Individuals with ADPKD may be unable to respond appropriately in the clearance of these small crystals. Previously, our lab has shown that ADPKD cyst lining epithelial cells exhibit increased levels of mTOR and STAT3 activity. This same activation of mTOR and STAT3 can be seen following calcium oxalate crystal deposition in both wild-type mice and rats. In addition to the increase in STAT3 and mTOR activity, there is a concomitant increase in tubule dilation. This dilation persists until crystals are no longer detected in kidneys along with a cessation of mTOR and STAT3 activity. Additionally, we demonstrate that the Han:SPRD and pck rat models of PKD exhibit an exacerbated renal phenotype following an increase in kidney microcrystals. Cyst number and cystic index increase following crystal deposition demonstrating that the mechanism of cystogenesis is crystal dependent. The discovery that crystals act as a trigger for cyst formation is an important step in elucidating the causal mechanism of cystogenesis in ADPKD and a critical step in creating effective preventative and palliative strategies.