Serine-arginine-rich protein kinase-1 inhibition for the treatment of diabetic retinopathy

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 322; no. 6; pp. H1014 - H1027
• Main Authors: Malhi, Naseeb K, Allen, Claire L, Stewart, Elizabeth, Horton, Katherine L, Riu, Federica, Batson, Jennifer, Amoaku, Winfried, Morris, Jonathan C, Arkill, Kenton P, Bates, David O
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2022
• Series: New Developments in Translational Microcirculatory Research
• Subjects: Angiogenesis; Animals; Arginine; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetic retinopathy; Diabetic Retinopathy - drug therapy; Edema; Eye; Humans; Hyperglycemia; Isoforms; Kinases; Macular Edema; Ophthalmic Solutions; Permeability; Protein kinase C; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases; Proteins; Rats; Retina; Retinopathy; Serine; Serine-Arginine Splicing Factors; Switches; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; endothelium; splicing; diabetic retinopathy; vascular permeability; VEGF
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/AJPHEART.00001.2022

Angiogenic VEGF isoforms are upregulated in diabetic retinopathy (DR), driving pathological growth and fluid leakage. Serine-arginine-rich protein kinase-1 (SRPK1) regulates VEGF splicing, and its inhibition blocks angiogenesis. We tested the hypothesis that SRPK1 is activated in diabetes, and an SRPK1 inhibitor (SPHINX31) switches VEGF splicing in DR and prevents increased vascular permeability into the retina. SRPK1 was activated by high glucose (HG), in a PKC-dependent manner, and was blocked by SPHINX31. HG induced release of SRSF1 from the nuclear speckles, which was also SRPK1 dependent, and increased retinal pigment epithelial (RPE) monolayer admittance, which was reversed by SRPK1 inhibition ( < 0.05). Diabetes increased retinal permeability and thickness after 14 days which was blocked by treatment with SPHINX31 eye drops ( < 0.0001). These results show that SRPK1 inhibition, administered as an eye drop, protected the retinal barrier from hyperglycemia-associated loss of integrity in RPE cells in vitro and in diabetic rats in vivo. A clinical trial of another SRPK1 inhibitor has now been initiated in patients with diabetic macular edema. VEGF-A b splicing is induced by hyperglycemia through PKC-mediated activation of SRPK1 in RPE cells, increasing their permeability and angiogenic capability. SRPK1 inhibitors can be given as eye drops to reduce retinal permeability and edema in diabetic retinopathy.