Investigating intracellular cholesterol biosynthesis as a regulator of polycystic kidney disease progression - Project Summary/Abstract Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the leading genetic cause of kidney disease, with an estimated economic burden of seven billion dollars annually. The only treatment to slow disease progression has risk of severe side effects. Thus, there is significant need to advance our knowledge of ADPKD pathogenesis to identify novel ways to slow cyst growth. We have discovered that sterol regulatory element binding proteins (SREBPs) may attenuate cyst growth. SREBP1/2 are the master transcriptional regulators of lipogenesis genes. Our preliminary studies show that reducing SREBP1/2 activity accelerates cyst growth in mouse models of PKD. Conversely activating SREBP1/2 signaling markedly slows cyst growth in mouse models of ADPKD and prolongs survival. These results are unexpected, considering that higher fatty acid (FA) synthesis or sphingolipids have been shown to aggravate PKD. However, in addition to lipids, SREBP1/2 also enhance cholesterol synthesis with SREBP2 being preferentially active at loci of genes in the cholesterol biosynthesis pathway. Indeed, we have discovered that cholesterol is reduced in mouse and human kidneys with PKD. We have also found that reduction of only Srebp2 also aggravates cyst growth, implicating the cholesterol pathway. Thus, while lipids such as FA and sphingolipids are deleterious, cholesterol species may in fact be beneficial in ADPKD. Based on these intriguing preliminary observations, we hypothesize that cholesterol plays a cyst- attenuating role in ADPKD. We will test this hypothesis in the following specific aims: 1)Determine if reducing intracellular cholesterol by inhibiting de novo synthesis or uptake aggravates ADPKD; 2) Determine if enhancing intracellular production of cholesterol slows ADPKD; 3) Identify cholesterol client proteins in ADPKD. In summary our studies will advance our understanding of metabolism in ADPKD and open new avenues of exploration for future therapeutic development targeting the cholesterol pathway.
