NBL1 Associates with Renal Phenotypes in Mice, but Partial Nbl1 Reduction Does Not Ameliorate Kidney Disease

Increased concentrations of neuroblastoma suppressor of tumorigenicity 1 (NBL1) in the blood have been associated with disease progression in diabetic kidney disease and IgA nephropathy. However, it is unclear whether NBL1 is a causal factor for kidney disease and what is driving these increased concentrations in the blood. To test this, we evaluated <i>Nbl1</i> heterozygous knockout (Nbl1 ^<i>+/-</i>) mice in two models of kidney injury, X-linked Alport syndrome (XLAS) and chronic low-dose cisplatin treatment and compared them to wild-type (WT) controls. In parallel, we assessed serum NBL1, kidney function and damage, and performed a genetic analysis for the drivers of NBL1 concentrations in two independent cohorts of genetically diverse Diversity Outbred mice with XLAS (DO-XLAS), analyzing each cohort separately. Serum NBL1 was consistently associated with reduced GFR across both DO-XLAS cohorts, while correlations with ACR were variable between cohorts, and not consistently replicated. In both XLAS and cisplatin models, partial reduction of NBL1 (~50%) in Nbl1 ^<i>+/-</i> mice did not alter GFR, ACR, or histological injury relative to WT controls. Genetic analysis of NBL1 concentrations in our DO-XLAS cohorts identified associations with loci on Chromosomes 4 and 17. Together, these findings indicate that elevated serum NBL1 reflects kidney injury and, under partial reduction, does not alter disease severity, consistent with NBL1 functioning as a biomarker rather than a causal driver of kidney disease.