Proximal Tubule‑Derived Semaphorin 3C Promotes Fibrosis in Adenine-Induced Tubulointerstitial Nephritis.

KEY POINTS: Proximal tubule‑derived semaphorin 3C functioned as a promoter of inflammation and fibrosis in adenine-induced tubulointerstitial nephritis. Semaphorin 3C acted on renal fibroblasts to enhance the expression of profibrotic markers and to promote proliferation. Thus, proximal tubule‑derived semaphorin 3C may represent a potential therapeutic target in tubulointerstitial nephritis.

BACKGROUND

Semaphorin 3C (SEMA3C) is a secreted protein that is essential for cardiovascular and renal development; however, its role in the development and progression of CKD remains unclear.

METHODS

We performed immunostaining for SEMA3C in human and murine kidneys. Subsequently, tamoxifen-inducible proximal tubule‑specific Sema3c functional knockout mice ( Ndrg1CreERT2/+ ; Sema3cflox/flox , PT- Sema3c FKO) were generated using the clustered regularly interspaced short palindromic repeats-Cas9 technique. To evaluate the renoprotective effects of PT- Sema3c FKO, we used two well-established models of CKD: the adenine-induced tubulointerstitial nephritis model and high-fat diet/streptozotocin-induced diabetic nephropathy (DN) model.

RESULTS

Immunostaining of human and murine kidneys showed high SEMA3C expression in the proximal tubules (PTs), particularly in human tubulointerstitial nephropathy. In adenine-induced tubulointerstitial nephritis, control (Ctrl) littermates ( Ndrg1+/+ ; Sema3cflox/flox ) showed increased Sema3c expression, whereas PT- Sema3c FKO mice exhibited markedly reduced Sema3c expression with attenuated fibrosis and inflammation. By contrast, in the high-fat diet/streptozotocin-induced DN model, renal Sema3c expression decreased in Ctrl mice after DN induction, and neither proteinuria nor fibrosis was ameliorated in PT- Sema3c FKO mice. In vitro , SEMA3C expression in PT cells was upregulated by TNF- α or TGF- β ; however, it was downregulated under glucotoxic conditions. SEMA3C stimulation of kidney fibroblasts induced profibrotic marker expression and proliferation.

CONCLUSIONS

PT-derived SEMA3C promotes inflammation and fibrosis in adenine-induced tubulointerstitial nephritis.