The key role of NLRP3 and STING in APOL1-associated podocytopathy.

Abstract

Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.

• Authors: Junnan Wu, Archana Raman, Nathan J Coffey, Xin Sheng, Joseph Wahba, Matthew J Seasock, Ziyuan Ma, Pazit Beckerman, Dorottya Laczkó, Matthew B Palmer, Jeffrey B Kopp, Jay J Kuo, Steven S Pullen, Carine M Boustany-Kari, Andreas Linkermann, Katalin Susztak
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 20 (10 15 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 34651582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein L1
• Membrane Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• STING1 protein, human
• Sting1 protein, mouse

Topics

• Animals
• Apolipoprotein L1 (genetics, physiology)
• Humans
• Kidney Diseases (etiology)
• Membrane Proteins (physiology)
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein (physiology)
• Podocytes (pathology)