Abstract P434: Role of Dusp5 in Hypertension Induced Chronic Renal Disease

Abstract

We recently identified 4 single nucleotide polymorphisms in Dusp5 in FHH as compared with Brown-Norway (BN) rats, two of which alter CpG sites and another one causes G155R mutation. We then created a Dusp5 knockout (KO) rat in the FHH.1 BN genetic background, in which a small region in Chr. 1 of BN rats containing 15 genes, including Dusp5 into the FHH rats. We found that knockout of Dusp5 enhances the myogenic response and autoregulation of cerebral circulation. In the present study, we evaluated whether Dusp5 also plays a role in the regulation renal function. The expression of Dusp5 was lower in FHH. 1 BN . Dusp5 KO rats in comparison to the FHH.1 BN rats. The levels of p-PKC and p-ERK1/2 were elevated in Dusp5 KO vs. FHH.1 BN rats. The blood pressure and urinary protein excretion was similar in FHH. 1 BN . Dusp5 KO (n = 43) and FHH.1 BN rats (n = 30) when they were at 12-week of age (114 ± 2 vs. 115 ± 1 mmHg and 32 ± 2 vs. 29 ± 3 mg/day). The autoregulation of RBF was similar in FHH.1 BN (n=22) and Dusp5 KO (n = 9) rats in response to elevation of MAP from 100 to 140 mmHg, but was impaired in FHH rats (n=21) that increased by 37.3 ± 2.3% when they were at 12-week of age. In response to an elevation in pressure from 60 to 120 mm Hg, the renal afferent arterioles constricted by 29 ± 2% and 11 ± 1%, respectively in Dusp5 KO (n = 6) in comparison to FHH.1 BN rats (n = 17). Blood pressure was similar in Dusp5 KO (n = 11) vs. FHH.1 BN rats (n = 14) after 3-week DOCA-salt treatment (169 ± 5 vs. 177 ± 5 mmHg). However, proteinuria was significantly reduced in Dusp5 KO rats (258 ± 22 mg/day, n = 12) in comparison to FHH.1 BN rats (338 ± 30 mg/day, n = 12). The renal injury induced by DOCA-salt was markedly reduced in Dusp5 KO vs. FHH.1 BN rats as the glomerular injury scores were 2.49 ± 0.03 vs. 2.54 ± 0.01; the areas of renal fibrosis were 5.5 ± 0.5% vs. 8.3 ± 0.3%; the areas of renal protein casts were 0.5 ± 0.2% vs. 2.4 ± 1.0% and renal arteriolar media-to-lumen ratios were 0.64 ± 0.03 vs. 0.81 ± 0.04, respectively. These results indicate that KO of Dusp5 enhances renal vascular function to protect against DOCA-salt hypertension induced chronic renal injury via activation of PKC/ERK signaling pathway. In conclusion, an activating mutation in Dusp5 may contribute to the impaired myogenic response and promote the development of chronic renal injury in FHH rats.