Striking differences in uromodulin excretion and expression, salt-sensitive hypertension, and renal injury in Dahl SS vs. BN and SS.BN1 consomic rats

Uromodulin (UMOD) is a protein made exclusively in the thick ascending limb. Clinical studies have demonstrated that rare missense mutations in UMOD result in autosomal dominant tubulointerstitial kidney diseases manifest by tubulointerstitial fibrosis (TIF), tubular cysts and a rapid progression to renal failure. In addition, several genome wide association studies reported that common single nucleotide polymorphisms in the UMOD gene are associated with an increased risk of chronic kidney disease (CKD) and hypertension. Interestingly, Dahl salt-sensitive (SS) rats exhibit many of the same pathologies observed in these clinical populations with alterations in UMOD.The goal of this study was to assess the qualitative and quantitative aspects of UMOD via western blotting, and the extent of SS hypertension and proteinuria in Dahl SS vs. a consomic rat strain in which chromosome 1 of the salt-resistant Brown-Norway (BN) rat, harboring the UMOD gene, has been introgressed into the Dahl SS background (SS.BN1). We hypothesized that differences in UMOD would be apparent in SS vs. SS.BN1 rats maintained on a low salt-diet and that the extent of SS hypertension and proteinuria would be attenuated in SS.BN1 vs SS rats. Western blot of urinary UMOD was performed in 16 week old SS (n=5), SS.BN1 (n=7) and BN (n=6) rats maintained on a low salt (LS) diet. BP (radiotelemetry) and proteinuria were assessed during LS feeding and during three weeks of high salt (HS) feeding in a different group of 8-10 week old SS (n=9) and SS.BN1 (n=8) rats.For western blotting, urine was normalized based on the protein concentration, and the density of the 85 kDa UMOD band in SS and SS.BN1 samples were normalized to the average density observed in BN rats. The UMOD band was 4.5 fold higher (pIn summary, these data demonstrate striking qualitative and quantitative differences in UMOD between SS and SS.BN1 rats. The pattern of UMOD expression in SS rats is consistent with that observed in some patient populations of UMOD associated kidney disease. Finally, the evidence that SS.BN1 rats, harboring the UMOD gene from BN rats, exhibit significant protection against SS hypertension and proteinuria is consistent with the notion that an alteration in UMOD function may, in part, be responsible for such pathologies in SS rats.