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Article

The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice

by
Kamila Zglejc-Waszak
1,*,
Agnieszka Korytko
2,
Bernard Kordas
2,
Andrzej Pomianowski
3,
Bogdan Lewczuk
4,
Joanna Wojtkiewicz
2,
Krzysztof Wąsowicz
5,
Izabella Babińska
5,
Konark Mukherjee
6 and
Judyta Karolina Juranek
2,*
1
Department of Anatomy and Histology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-085 Olsztyn, Poland
2
Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-085 Olsztyn, Poland
3
Internal Medicine Department, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
4
Department of Histology and Embryology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
5
Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
6
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(22), 11182; https://doi.org/10.3390/ijms262211182
Submission received: 3 October 2025 / Revised: 3 November 2025 / Accepted: 13 November 2025 / Published: 19 November 2025
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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Abstract

Diabetic peripheral neuropathy (DPN) is a serious consequence of prolonged hyperglycemia and contributes to the morbidity associated with diabetes. Hyperglycemia enhances the non-enzymic glycation of proteins and the accumulation of Advanced Glycation End Products (AGEs). We employed a diabetic mouse model lacking both Diaph1 and RAGE to elucidate the role of RAGE-Diaph1 signaling in the pathogenesis of DPN. We demonstrate that simultaneous deletion of Diaph1 and RAGE did not change the course or the intensity of hyperglycemia-induced weight loss in mice. However, abrogating RAGE-Diaph1 signaling affects actin cytoskeleton remodeling rates in nerve axons by altering the ratio of the actin-regulating molecules cofilin and profilin. Our experimental results suggest that the loss of RAGE-Diaph1 signaling protects neurons from hyperglycemic conditions. We observed a beneficial effect of abolishing RAGE-Diaph1 signaling on the axonal structure of neuropathic nerves. In addition, we observed that abolishing RAGE-Diaph1 signaling improved motor nerve conduction velocity in the sciatic nerves of hyperglycemic mice. Our data indicate that RAGE-Diaph1 signaling is likely enhanced in chronic hyperglycemia, resulting in aberrant actin dynamics in nerve axons. These defective actin dynamics play a key role in the progression of DPN, leading to structural and functional loss in peripheral nerves.
Keywords: cytoskeleton; type 1 diabetes; neuropathy; sciatic nerve; Diaph1; RAGE cytoskeleton; type 1 diabetes; neuropathy; sciatic nerve; Diaph1; RAGE

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MDPI and ACS Style

Zglejc-Waszak, K.; Korytko, A.; Kordas, B.; Pomianowski, A.; Lewczuk, B.; Wojtkiewicz, J.; Wąsowicz, K.; Babińska, I.; Mukherjee, K.; Juranek, J.K. The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice. Int. J. Mol. Sci. 2025, 26, 11182. https://doi.org/10.3390/ijms262211182

AMA Style

Zglejc-Waszak K, Korytko A, Kordas B, Pomianowski A, Lewczuk B, Wojtkiewicz J, Wąsowicz K, Babińska I, Mukherjee K, Juranek JK. The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice. International Journal of Molecular Sciences. 2025; 26(22):11182. https://doi.org/10.3390/ijms262211182

Chicago/Turabian Style

Zglejc-Waszak, Kamila, Agnieszka Korytko, Bernard Kordas, Andrzej Pomianowski, Bogdan Lewczuk, Joanna Wojtkiewicz, Krzysztof Wąsowicz, Izabella Babińska, Konark Mukherjee, and Judyta Karolina Juranek. 2025. "The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice" International Journal of Molecular Sciences 26, no. 22: 11182. https://doi.org/10.3390/ijms262211182

APA Style

Zglejc-Waszak, K., Korytko, A., Kordas, B., Pomianowski, A., Lewczuk, B., Wojtkiewicz, J., Wąsowicz, K., Babińska, I., Mukherjee, K., & Juranek, J. K. (2025). The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice. International Journal of Molecular Sciences, 26(22), 11182. https://doi.org/10.3390/ijms262211182

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