Suppression of microRNA-29 Expression by TGF-β1 Promotes Collagen Expression and Renal Fibrosis

TLDR

Renal fibrosis is driven by extracellular matrix deposition in the glomerulus and interstitium, yet the underlying mechanisms remain incompletely understood, and TGF‑β1’s modulation of microRNAs suggests a potential role for miRNAs in this process. The study aimed to determine how TGF‑β1 affects microRNA expression and collagen synthesis in proximal tubular cells, mesangial cells, and podocytes. Researchers exposed these renal cell types to TGF‑β1 and assessed changes in miRNA levels and collagen production. TGF‑β1 down‑regulates the miR‑29 family, leading to increased collagen I and IV expression and ECM deposition, while ectopic miR‑29 suppresses these collagens and fasudil restores miR‑29 levels, indicating that targeting miR‑29 may mitigate renal fibrosis.

Abstract

Synthesis and deposition of extracellular matrix (ECM) within the glomerulus and interstitium characterizes renal fibrosis, but the mechanisms underlying this process are incompletely understood. The profibrotic cytokine TGF-β1 modulates the expression of certain microRNAs (miRNAs), suggesting that miRNAs may have a role in the pathogenesis of renal fibrosis. Here, we exposed proximal tubular cells, primary mesangial cells, and podocytes to TGF-β1 to examine its effect on miRNAs and subsequent collagen synthesis. TGF-β1 reduced expression of the miR-29a/b/c/family, which targets collagen gene expression, and increased expression of ECM proteins. In both resting and TGF-β1-treated cells, ectopic expression of miR-29 repressed the expression of collagens I and IV at both the mRNA and protein levels by targeting the 3'untranslated region of these genes. Furthermore, we observed low levels of miR-29 in three models of renal fibrosis representing early and advanced stages of disease. Administration of the Rho-associated kinase inhibitor fasudil prevented renal fibrosis and restored expression of miR-29. Taken together, these data suggest that TGF-β1 inhibits expression of the miR-29 family, thereby promoting expression of ECM components. Pharmacologic modulation of these miRNAs may have therapeutic potential for progressive renal fibrosis.