Abstract 056: Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension Induced Chronic Kidney Disease

Abstract

Dual-specificity protein phosphatase 5 (Dusp5) is a member of serine-threonine phosphatase family that regulates intracellular signal transduction by dephosphorylating ERK1/2. We previously generated Dusp5 zinc-finger knockout (KO) rats and found that KO of Dusp5 enhances myogenic response of middle cerebral artery and autoregulation of cerebral blood flow. This study investigated whether Dusp5 KO also improves renal hemodynamics and protects against hypertension-induced chronic kidney disease (CKD). Renal tissue expression of Dusp5 was decreased and levels of phosphorylated ERK1/2 (p-ERK1/2) and p-PKC enhanced in KO rats. Blood pressure increased similarly to 180 mmHg in both WT and Dusp5 KO rats treated with DOCA/salt. KO of Dusp5 enhanced autoregulation of renal blood flow (RBF increased by 12.1 ± 4.1% vs. 32.7 ± 4.7% when MAP increased from 100 to 180 mmHg, p<0.05) and reduced renal vascular remodeling compared with WT rats (0.64±0.03 vs. 0.94±0.06 wall-to-lumen ratio, p<0.05). Improvement in renal hemodynamics in hypertensive Dusp5 KO vs. WT rats was associated with decreased proteinuria (226.71 ± 23.82 vs. 337.62 ± 30.41 mg/day, p<0.05) and protein cast formation in the renal corticomedullary region (1.01 ± 0.17% vs. 2.4 ± 0.51%, p<0.05). The degree of glomerular injury was reduced (2.22 ± 0.04 vs. 3.12 ± 0.04, p<0.05) and nephrin expression was greater in hypertensive Dusp5 KO rats vs. WT rats. Hypertension-induced renal fibrosis was attenuated in Dusp5 KO rats (5.32 ± 0.6% vs. 9.90 ± 0.7%, p<0.01) in association with decreased MCP-1 expression, reduced ED-1 + macrophage infiltration, down-regulated TGF-β1 expression, and attenuated fibrosis-related epithelial-mesenchymal transition (EMT) in the kidney (decreased expression of α-SMA and vimentin, and increased expression of E-cadherin). In conclusion, these results indicate that KO of Dusp5 protects against hypertension-induced proteinuria and renal fibrosis by enhancing renal hemodynamics and reducing vascular remodeling, glomerular injury, macrophage infiltration, TGF-β1 expression and EMT in the kidney. Thus, targeting Dusp5 may offer a novel approach for treating or preventing hypertension-induced CKD.