2. Academic Validation
  3. Kisspeptin-54 confers renal protection in diabetic nephropathy by ameliorating endothelial permeability through ZEB1 inhibition

Kisspeptin-54 confers renal protection in diabetic nephropathy by ameliorating endothelial permeability through ZEB1 inhibition

  • Tissue Cell. 2026 Aug:101:103503. doi: 10.1016/j.tice.2026.103503.
Lichao Gao 1,  Qiang Lv 2,  Yujie Wang 3,  Dongmei Zhang 3,  Wenfei Ding 3,  Ling Cao 3,  Santao Ou 3
Affiliations

Affiliations

  • 1 Department of Nephrology, Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou City, Sichuan Province 646000, China; Department of Nephrology, Sichuan Clinical Research Center for Nephropathy, Chengdu City, Sichuan Province 610000, China. Electronic address: [email protected].
  • 2 Luzhou People's Hospital, Luzhou City, Sichuan Province 646000, China.
  • 3 Department of Nephrology, Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou City, Sichuan Province 646000, China; Department of Nephrology, Sichuan Clinical Research Center for Nephropathy, Chengdu City, Sichuan Province 610000, China.
PMID: 41950743 DOI: 10.1016/j.tice.2026.103503
Abstract

Background: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). A central pathological feature is the breakdown of the glomerular endothelial barrier. Although the Kisspeptin-54/GPR54 pathway is known to regulate vascular function, its specific role and mechanism in DN-related renal endothelial damage are unclear.

Methods: This study used db/db mice (type 2 DN model) and human renal glomerular endothelial cells (HrGECs) exposed to high glucose (HG). We measured pathway components, assessed barrier function via albumin excretion and electrical resistance, and investigated mechanisms through loss-of-function (siRNA), inhibition (ERK Inhibitor), and rescue (ZEB1 overexpression) experiments.

Results: The Kisspeptin-54/GPR54 pathway was impaired in DN models. Kisspeptin-54 treatment in mice restored the junction protein ZO-1, reduced albuminuria and serum creatinine. In HG-exposed cells, it concentration-dependently improved barrier integrity. Mechanistically, Kisspeptin-54 suppressed the upregulation of the transcriptional repressor ZEB1. This effect was blocked by ERK inhibition and required GPR54, as siRNA knockdown abolished the benefits. Overexpression of ZEB1 reversed the protection provided by Kisspeptin-54.

Conclusion: Our findings demonstrate that Kisspeptin-54 alleviates DN by preserving renal endothelial barrier function. This action is mediated through GPR54 to inhibit ZEB1, thereby preventing ZO-1 repression. This work defines the Kisspeptin-54/GPR54-ZEB1-ZO-1 axis as a potential therapeutic target for DN.

Keywords

Diabetic nephropathy; GPR54; Kisspeptin-54; Renal endothelial barrier; ZEB1; ZO-1.

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