Hyperuricemia and crystal-induced nephropathies

• Applicant: Dr. Stefanie Steiger
• Subject Area: Nephrology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 319531248

Uric acid (UA) is the end-product of the purine metabolism in humans and higher primates. Most other mammals can degrade UA further to water soluble allantoin with the enzyme uricase. However, in humans and higher primates, mutations in the uricase gene occurred during evolution and, making the enzyme nonfunctional, resulted in higher levels of serum UA. Hyperuricemia (HU) is defined as the accumulation of serum UA (>6.8 mg/dl), and it develops due to UA overproduction, underexcretion, or both. Persistent HU is central to the pathogenesis of diseases such as Lesch-Nyhan syndrome, gouty arthritis, and kidney stone disease. In addition, epidemiological reports document the association between persistent HU and cardiovascular disease, obesity or chronic kidney disease (CKD) progression but the molecular mechanisms that could imply causality in these contexts remain uncertain.Crystals including calcium oxalate and UA crystals act as danger-associated molecular patterns. They can trigger an inflammatory response associated with leukocyte recruitment, neutrophil extracellular trap formation and fibrosis – such as in patients with gouty arthritis, nephrocalcinosis or UA crystal-induced nephropathy. However, the overall functional importance of HU in vitro and in vivo remains controversial due to the lack of a suitable animal model and the use of clinically irrelevant sUA concentrations for in vitro experiments. Over the past three years, I have established a novel transgenic mouse model of HU with or without CKD that mimics the range of HU in humans more accurately. This animal model was used to investigate the immunomodulatory effect of HU during sterile inflammation and acute kidney injury, as well as the role of renal UA crystal granulomas on CKD progression.The goal of this DFG project grand extension is to finish and finalize the current research topics within the next 12 months. The specific aims are as follow: (1) To identify the intracellular signaling pathways that are altered by sUA in human monocytes; (2) To investigate the role of sUA in human macrophages regarding mitochondrial respiration and inflammation during AKI in vitro; (3) To perform single-cell RNA-sequencing of kidney cells from mice with UA crystal granulomas; (4) To investigate the impact of the genetic background on renal CaOx crystal deposition in vivo; and (5) To breed the generated Uox-deficient mice with Alb-creERT2 mice to generate an inducible deletion system of uricase (Uox gene). In this context, a more detailed understanding of the cellular and molecular mechanisms will not only provide a more comprehensive knowledge of the disease pathogenesis, but potentially guide us to novel targets and prognostic markers that underpin therapeutic approaches for HU and crystal-related diseases.

• DFG Programme: Research Grants