HuR Inhibition Attenuates Hypertension and Fibrosis in Chronic Kidney Disease

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Abstract
BACKGROUND: Upregulation of the RNA-binding protein HuR (human antigen R) has been reported in patients with chronic kidney disease (CKD), but its pathogenic role remains incompletely understood. We hypothesized that HuR promotes renal and vascular injury in hypertensive CKD and that pharmacological inhibition of HuR attenuates disease progression. We therefore investigated the role of HuR in deoxycorticosterone acetate (DOCA) plus Ang II (angiotensin II)-induced CKD and evaluated the therapeutic efficacy of the HuR inhibitor, KH3 . METHODS: Male mice underwent uninephrectomy followed by DOCA+Ang II infusion with 1% NaCl in drinking water and were treated with KH3 or vehicle for 3 weeks. Control mice received saline without DOCA or Ang II. RESULTS: DOCA+Ang II markedly increased HuR expression in circulating exosomes and kidney tissues, which was attenuated by KH3 treatment. KH3 reduced albuminuria, improved renal function, and attenuated kidney hypertrophy, glomerular, and tubulointerstitial fibrosis. These renoprotective effects were associated with reduced podocyte and tubular injury, decreased macrophage infiltration, and suppression of NF-κB (nuclear factor-kappa B) p65, Nox2 (NADPH oxidase 2), AKT (protein kinase B) phosphorylation, TGFβ1 (transforming growth factor β1), and Wisp1 (WNT1-inducible signaling pathway protein 1) signaling. KH3 also partially lowered arterial blood pressure in DOCA+Ang II–treated mice. Further studies in vascular smooth muscle cells and mesenteric resistance arteries suggested that HuR inhibition may suppress vascular profibrotic signaling associated with SGLT2 (sodium-glucose cotransporter 2). CONCLUSIONS: HuR is upregulated in renal and vascular tissues in DOCA+Ang II–induced CKD and contributes to renal inflammation, oxidative stress, fibrosis, and vascular dysfunction. Pharmacological inhibition of HuR attenuates renal and vascular injury, supporting HuR as a promising therapeutic target for CKD.

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