Pathophysiological and therapeutic implications of C-type natriuretic peptide/cyclic GMP signaling in pulmonary fibrosis

Rene Weyer; Katharina Völker; Tamara Potapenko; Lisa Krebes; Marco Abesser; Anna-Lena Friedrich; Eva Lessmann; Ali Khadim; Clemens Ruppert; Elie El Agha; Dalia Sheta; Andreas Beilhack; Daniel V. Santi; Eric L. Schneider; Michaela Kuhn; Swati Dabral

doi:10.1172/jci.insight.196812

Pathophysiological and therapeutic implications of C-type natriuretic peptide/cyclic GMP signaling in pulmonary fibrosis

Rene Weyer,¹ Katharina Völker,¹ Tamara Potapenko,¹ Lisa Krebes,¹ Marco Abesser,¹ Anna-Lena Friedrich,¹ Eva Lessmann,¹ Ali Khadim,² Clemens Ruppert,³ Elie El Agha,² Dalia Sheta,⁴ Andreas Beilhack,⁴ Daniel V. Santi,⁵ Eric L. Schneider,⁵ Michaela Kuhn,¹ and Swati Dabral¹

Published January 7, 2026 - More info

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Abstract

Activation of lung fibroblasts in response to epithelial injury and inflammation provokes pulmonary fibrosis (PF). Endogenous molecular brakes counteracting fibroblast activity can be targets for therapies. Preclinical studies of synthetic C-type natriuretic peptide (CNP) indicated that this hormone might provide such a brake. As shown here, CNP exerts antifibrotic effects in cultured lung fibroblasts as well as precision cut lung slices from patients with PF, supporting clinical relevance. Therefore, augmenting or supplementing endogenous CNP could improve the treatment of such patients. To unravel whether paracrine CNP counteracts inflammation-driven PF, we studied mice with fibroblast-restricted knock-out of guanylyl-cyclase-B (GC-B), its cGMP-synthesizing receptor. Fibroblast GC-B-KO mice had enhanced bleomycin-induced lung inflammation, with increased expression of proinflammatory, profibrotic cytokines. Nevertheless, subsequent PF was not exacerbated. Molecular studies revealed that inflammation led to inhibition of CNP signaling in resident myofibroblasts, namely GC-B downregulation and induction of CNP/cGMP-degrading pathways. Despite this, a single subcutaneous injection of the recently developed long-acting CNP analog, MS~[Gln^6,14]CNP-38, abrogated experimental lung inflammation and fibrosis. We conclude that CNP signaling in lung fibroblasts has anti-inflammatory and antifibrotic effects. Attenuation of this endogenous brake participates in the pathogenesis of PF and rescuing this pathway with long-acting CNP-analogs may have therapeutic potential.

Pathophysiological and therapeutic implications of C-type natriuretic peptide/cyclic GMP signaling in pulmonary fibrosis

Rene Weyer,¹ Katharina Völker,¹ Tamara Potapenko,¹ Lisa Krebes,¹ Marco Abesser,¹ Anna-Lena Friedrich,¹ Eva Lessmann,¹ Ali Khadim,² Clemens Ruppert,³ Elie El Agha,² Dalia Sheta,⁴ Andreas Beilhack,⁴ Daniel V. Santi,⁵ Eric L. Schneider,⁵ Michaela Kuhn,¹ and Swati Dabral¹

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Pathophysiological and therapeutic implications of C-type natriuretic peptide/cyclic GMP signaling in pulmonary fibrosis

Rene Weyer,1 Katharina Völker,1 Tamara Potapenko,1 Lisa Krebes,1 Marco Abesser,1 Anna-Lena Friedrich,1 Eva Lessmann,1 Ali Khadim,2 Clemens Ruppert,3 Elie El Agha,2 Dalia Sheta,4 Andreas Beilhack,4 Daniel V. Santi,5 Eric L. Schneider,5 Michaela Kuhn,1 and Swati Dabral1

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Rene Weyer,¹ Katharina Völker,¹ Tamara Potapenko,¹ Lisa Krebes,¹ Marco Abesser,¹ Anna-Lena Friedrich,¹ Eva Lessmann,¹ Ali Khadim,² Clemens Ruppert,³ Elie El Agha,² Dalia Sheta,⁴ Andreas Beilhack,⁴ Daniel V. Santi,⁵ Eric L. Schneider,⁵ Michaela Kuhn,¹ and Swati Dabral¹