NBL1 Associates with Renal Phenotypes in Mice, but Partial Nbl1 Reduction Does Not Ameliorate Kidney Disease: Male Nbl1 HET or WT Mice Treated with Cisplatin or PBS
Background: Increased concentrations of neuroblastoma suppressor of tumorgenicity 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. Methods: We tested causality of NBL1 by knocking out Nbl1 in two different mouse models of kidney disease (X-linked Alport Syndrome (XLAS) and low-dose cisplatin treatment) and performed a genetic analysis for the drivers of NBL1 concentrations in two independent cohorts of genetically diverse (DO) mice with X-linked Alport Syndrome (DO-XLAS). Results: Significant correlations were found between NBL1 concentrations in the blood and both GFR and ACR in DO-XLAS mice. However, XLAS mice with only one functional Nbl1 allele and reduced NBL1 concentrations had similar GFR and ACR compared to Nbl1 wildtype animals. Similarly, there was no difference between animals with one or two functional Nbl1 alleles after chronic low-dose cisplatin treatment. Genetic analysis of NBL1 concentrations in our DO-XLAS cohorts identified associations with loci on Chromosomes 4 and 17, with Clcnka, and MHC2 as potential candidates. Conclusion: Increased NBL1 in blood is a marker for different forms of kidney disease but is not a causal factor. Overall design: Male Nbl1 HET or WT mice treated with Cisplatin or PBS (Control) for 4 consecutive weeks starting at 8 weeks of age (all mice are on the B6 background). Bulk RNA-seq of kidneys collected 3 days post treatment at 11-weeks of age.