Tubular La Ribonucleoprotein 7 Suppresses TGF- β /SMAD3 Signaling and Attenuates Kidney Fibrogenesis

LARP7 suppresses TGF- β /SMAD3-driven fibrosis by sequestering CDK9, which inhibits SMAD3 T179 phosphorylation and profibrotic transcription. TGF- β 1 represses LARP7 expression in injured tubules, establishing a self-reinforcing loop that amplifies and sustains fibrogenic signaling. Tubule-specific LARP7 restoration interrupts this vicious cycle, attenuates SMAD3 activity, and confers protection against kidney fibrosis in vivo .

TGF- β 1/SMAD3 signaling drives organ fibrosis, underscoring the need to identify its endogenous regulators for precision therapies. LARP7, a core component of the 7SK snRNP complex that sequesters cyclin-dependent kinase 9, has an unexplored role in kidney fibrosis and a potential interplay with TGF- β /SMAD3 signaling.

Single-cell and spatial transcriptomic analyses combined with immunostaining of human kidney biopsies were used to investigate the association between LARP7 and TGF- β /SMAD3 signaling in patients with CKD. In vivo and in vitro models evaluated the expression profile of LARP7 after insults and its contribution to TGF- β /SMAD3 signaling and fibrosis postinjury.

We demonstrated that LARP7, abundantly expressed in normal tubules, was downregulated in CKD patients and inversely correlated with TGF- β /SMAD3 activation. This expression pattern was conserved across ischemic, toxic, and obstructive fibrosis models and recapitulated in TGF- β 1-treated tubular epithelial cells, indicating a general link between LARP7 downregulation and enhanced TGF- β /SMAD3 signaling. Further loss-of-function and gain-of-function in vitro studies confirmed that LARP7 acted as a specific disruptor of SMAD3 linker region (T179) phosphorylation-an event that coincided with C -terminal phosphorylation and amplified SMAD3 transcriptional activity. LARP7 mediated this by sequestering CDK9 within the 7SK snRNP, thereby preventing CDK9-SMAD3 interaction and consequently inhibiting SMAD3 T179 phosphorylation and profibrotic transcription. TGF- β 1 itself suppressed LARP7 expression, completing a self-reinforcing feedback loop that perpetuates TGF- β /SMAD3 signaling in injured tubular epithelial cells. Further in vivo studies showed that tubule-specific Larp7 deletion exacerbated kidney fibrosis after ischemic injury, whereas its overexpression, either preventatively (prefibrosis in an obstructive model) or therapeutically (postfibrosis in ischemic and toxic models), attenuated functional decline and halted fibrotic progression.

Our findings revealed tubular LARP7 as a key negative regulator of TGF- β /SMAD3-driven kidney fibrogenesis. Targeted overexpression of LARP7 in injured tubular epithelial cells attenuated TGF- β 1/SMAD3 signaling and conferred protection against postinjury fibrosis.