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Updated: Sep 12, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
SRPK1 is a significant factor in driving the progression of diabetic kidney fibrosis
Shichao Han1, Shuaijun Ma1, Kepu Liu1
1Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
Background:
Diabetic nephropathy leads to renal fibrosis via excessive ECM accumulation. Current therapies lack specificity, highlighting the need to identify targets like SRPK1, whose role in diabetic kidney fibrosis remains unclear.
Methods:
We investigated SRPK1's function using a streptozotocin-induced diabetic nephropathy mice model and administered the selective SRPK1 inhibitor SRPIN340. Histological, biochemical, and molecular analyses were performed to assess ECM deposition, renal function, and fibrotic marker expression. Additionally, Western blotting and immunohistochemistry were utilized to explore the involvement of the NF-κB/NLRP3 signaling pathway.
Results:
SRPK1 expression was significantly elevated in fibrotic kidneys, correlating with increased ECM components (collagen I/III, fibronectin) and reduced renal function. SRPIN340 treatment markedly alleviated ECM accumulation, improved glomerular filtration rate, and suppressed fibrotic markers (α-SMA, TGF-β). Mechanistically, SRPK1 activation promoted NF-κB/NLRP3 pathway activation, leading to inflammatory cytokine release (IL-1β, TNF-α) and fibrosis. Inhibition of SRPK1 via SRPIN340 abrogated these effects, suggesting a causal role for SRPK1 in fibrotic progression.
Conclusion:
SRPK1 activates NF-κB/NLRP3 pathway, promoting ECM synthesis and inflammation in diabetic nephropathy; SRPIN340 reduces fibrosis, highlighting SRPK1 as a therapeutic target.
Insights
Diabetic nephropathy causes kidney fibrosis by increasing extracellular matrix (ECM). Targeting SRPK1 with SRPIN340 reduces fibrosis by inhibiting the NF-κB/NLRP3 pathway, offering a potential therapeutic strategy.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- Diabetic nephropathy is characterized by excessive extracellular matrix (ECM) accumulation, leading to renal fibrosis.
- Current treatments for diabetic nephropathy lack specificity.
- The role of SRPK1 in the pathogenesis of diabetic kidney fibrosis is not well understood.
Purpose of the Study:
- To investigate the role of SRPK1 in diabetic nephropathy.
- To evaluate the therapeutic potential of the SRPK1 inhibitor SRPIN340 in a mouse model of diabetic kidney disease.
Main Methods:
- A mouse model of streptozotocin-induced diabetic nephropathy was used.
- Mice were treated with the selective SRPK1 inhibitor SRPIN340.
- Histological, biochemical, and molecular analyses, including Western blotting and immunohistochemistry, were performed to assess renal fibrosis and related signaling pathways (NF-κB/NLRP3).
Main Results:
- SRPK1 expression was elevated in fibrotic kidneys and correlated with ECM deposition and impaired renal function.
- SRPIN340 treatment significantly reduced ECM accumulation, improved glomerular filtration, and suppressed fibrotic markers.
- SRPK1 activation promoted the NF-κB/NLRP3 pathway, leading to inflammation and fibrosis, effects which were abrogated by SRPIN340.
Conclusions:
- SRPK1 plays a critical role in promoting ECM synthesis and inflammation in diabetic nephropathy via the NF-κB/NLRP3 pathway.
- SRPK1 inhibition with SRPIN340 effectively reduces renal fibrosis.
- SRPK1 represents a promising therapeutic target for diabetic kidney disease.
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