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 (DKD) 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 Nbl1 heterozygous knockout (Nbl1^+/-) mice in two models of kidney injury, X-linked Alport syndrome (XLAS) and chronic low-dose cisplatin treatment, and compared them with 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 glomerular filtration rate (GFR) across both DO-XLAS cohorts, whereas correlations with albumin-to-creatinine ratio (ACR) were variable between cohorts, and not consistently replicated. In both XLAS and cisplatin models, partial reduction of NBL1 (∼50%) in Nbl1^+/- 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.NEW & NOTEWORTHY Elevated NBL1 in blood correlates with end-stage kidney disease in humans with diabetic kidney disease. NBL1 also correlates with renal phenotypes in a cohort of genetically diverse mice with X-linked Alport syndrome. Studies in two different mouse models of kidney disease reveal that elevated NBL1 is not causal to kidney injury, positioning NBL1 as a biomarker with potential applicability across etiologies and clarifying its role as a consequence of renal pathology.