The Role of the Inflammasome in Hyperoxaluric Kidney Disease

• Applicant: Professor Dr. Felix Knauf
• Subject Area: Nephrology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258451658

Oxalate nephropathy can result from hyperoxaluria associated with overproduction of oxalate (primary hyperoxalurias) or secondary to excess absorption of dietary oxalate (enteric hyperoxaluria). A new mouse model of enteric hyperoxaluria has been established that results in chronic oxalate nephropathy with tubular calcium-oxalate crystal deposition and a profound inflammatory response surrounding crystals. Kidney inflammation correlated inversely with renal function leading to the hypothesis that the inflammasome may be involved in the pathogenesis of hyperoxaluric kidney disease. NALP3 has been implicated in other crystal-associated diseases such as gout and silicosis. Nalp3-null mice were protected from chronic oxalate nephropathy and mortality when tested in the model of enteric hyperoxaluria, strongly suggesting that crystal induced inflammation rather than tubular crystal obstruction is of major importance in the pathogenesis of hyperoxaluric kidney disease. The general goal of this project is to define the mechanisms by which Nalp3-null mice are protected from chronic oxalate nephropathy. In addition, the novel concept that plasma oxalate below the level of systemic oxalosis promotes the progression of chronic kidney disease (CKD) will be examined. To accomplish these goals, the following specific aims will be pursued: 1. Downstream and upstream targets to mitigate chronic oxalate nephropathy will be identified in vivo. The importance of specific cytokines such as Interleukin-1alpha and Interleukin-1beta in responding to calcium-oxalate mediated inflammation will be evaluated. The susceptibility to oxalate nephropathy of mice deficient in these key proteins will be tested, as will the effects of pharmacological inhibition of these pathways. The role of TOLL-like receptors in triggering the priming signal for calcium-oxalate induced NALP3 activation will be examined. 2. In a mouse model of chronic kidney disease we will test the hypothesis that plasma oxalate levels as observed in humans with CKD accelerates the progression of CKD. In follow up studies we will test whether these subtle elevations in plasma oxalate can activate the inflammasome to drive the progression of CKD. Together, the proposed studies will define the role of the inflammasome in oxalate-associated kidney disease. Identification of the mechanisms by which the inflammasome contributes to the pathogenesis of these disorders will allow the development of targeted therapeutic interventions to maintain acute and long-term kidney health.

• DFG Programme: Research Grants