HuR inhibition attenuates hypertension and fibrosis in chronic kidney disease

Background Elevated RNA-binding protein HuR has been reported in patients with chronic kidney disease (CKD), but its specific pathogenic role remains unclear. Here, we investigated HuR involvement in progressive CKD induced by deoxycorticosterone acetate (DOCA) plus angiotensin II (Ang II) in mice and evaluated the therapeutic efficacy and mechanisms of the HuR inhibitor KH3.

Adult male mice underwent uninephrectomy and were subjected to DOCA + Ang II infusion with 1% NaCl in drinking water. Mice were then treated with KH3 or vehicle for 3 weeks. Control mice received saline injections without DOCA and Ang II infusion.

DOCA + Ang II infusion markedly increased HuR expression in circulating exosomes and kidney tissues, which was attenuated by KH3. KH3 halted the progression of albuminuria and improved renal function, and reduced kidney hypertrophy and glomerular and tubulointerstitial fibrosis compared with untreated DOCA + Ang II mice. These improvements were associated with reduced podocyte and tubular injury. KH3 also decreased renal macrophage infiltration and suppressed NF-κBp65, Nox2, AKT phosphorylation, TGF-β1, and Wisp1, consistent with reduced inflammation, oxidative stress, and fibrosis. In addition, KH3 partially lowered arterial blood pressure in DOCA + Ang II–infused mice, an effect that may involve suppression of SGLT2-associated profibrotic vascular responses, as supported by studies in cultured VSMCs and mesenteric resistance arteries.

HuR is upregulated in DOCA + Ang II–induced renal and vascular injury and contributes to hypertensive, inflammatory, oxidative, and fibrotic responses in CKD. Pharmacologic inhibition of HuR-RNA interactions represents a promising therapeutic strategy for CKD. What Is New?This study identifies the RNA-binding protein HuR (ELAVL1) as a previously unrecognized upstream post-transcriptional regulator of blood pressure in hypertensive chronic kidney disease. We demonstrate for the first time that pharmacologic disruption of HuR–RNA interactions lowers arterial blood pressure in vivo. In addition, we uncover a novel HuR–SGLT2–vascular smooth muscle cell (VSMC) signaling axis, revealing that HuR regulates inducible vascular SGLT2 expression and Ang II–mediated vasoconstrictive responses. What Is Relevant?Hypertension in CKD arises from integrated renal and vascular dysfunction that is incompletely controlled by current therapies. Our findings are highly relevant because we identify HuR as a nodal post-transcriptional regulator that coordinates renal injury, vascular inflammation, and smooth muscle contractility, rather than acting within a single cell type or signaling pathway. Clinical and Pathophysiological Implication These data support a model in which HuR-driven RNA regulatory programs amplify Ang II–dependent vascular hypercontractility and hypertension in CKD. Therapeutic targeting of HuR–RNA interactions represents a novel antihypertensive strategy that may complement renin–angiotensin–aldosterone system (RAAS) blockade and provides mechanistic insight into the blood pressure–lowering and vascular protective effects of SGLT2 inhibitors, including in non-diabetic CKD. Competing Interest Statement The authors have declared no competing interest.