METANEPHRIC GRAFT DEVELOPMENT UNDER DIABETES AND HIF-PHD INHIBITION TOWARD XENOGENEIC RENAL REGENERATIVE THERAPY

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https://storage.unitedwebnetwork.com/files/1099/806e5b5d8d58acaae3f961c60ce872d6.pdf

Abstract Title *

METANEPHRIC GRAFT DEVELOPMENT UNDER DIABETES AND HIF-PHD INHIBITION TOWARD XENOGENEIC RENAL REGENERATIVE THERAPY

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Co-author 1

Nagisa Koda nkohda@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology & Hypertension, Department of Internal Medicine Tokyo Japan *

Co-author 2

Kei Matsumoto kmatsumoto@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology & Hypertension, Department of Internal Medicine Tokyo Japan -

Co-author 3

Toyoshi Seito sentkn@jikei.ne.jp Department of Urology Graduate School of Medicine, The University of Tokyo Tokyo Japan -

Co-author 4

Hinari Ohashi hinari0421@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology & Hypertension, Department of Internal Medicine Tokyo Japan -

Co-author 5

Takafumi Kuroda h25ms-kuroda@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology & Hypertension, Department of Internal Medicine Tokyo Japan -

Co-author 6

Takumi Ikeda h25ms-ikeda@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology & Hypertension, Department of Internal Medicine Tokyo Japan -

Co-author 7

Shutaro Yamamoto shutaro-yamamoto.urology@jikei.ac.jp Department of Urology The Jikei University School of Medicine Tokyo Japan -

Co-author 8

Keita Morimoto keita-m@jikei.ac.jp Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Co-author 9

Yuka Inage uzuka@jikei.ac.jp Department of Pediatrics The Jikei University School of Medicine Tokyo Japan -

Co-author 10

Yatsumu Saito h19ms-saito@jikei.ac.jp Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Co-author 11

Shohei Fukunaga korocelica@gmail.com Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Co-author 12

Toshinari Fujimoto ms05-fujimoto@jikei.ac.jp Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Co-author 13

Susumu Tajiri s.tajiri@jikei.ac.jp Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Co-author 14

Shuichiro Yamanaka shu.yamanaka@jikei.ac.jp Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Co-author 15

Takashi Yokoo tyokoo@jikei.ac.jp Division of Nephrology & Hypertension, Department of Internal Medicine The Jikei University School of Medicine Tokyo Japan -

Introduction

Chronic kidney disease (CKD) affects over 800 million people worldwide, and diabetic nephropathy is the leading cause of dialysis in Japan. Once end-stage renal failure occurs, dialysis is required, severely reducing quality of life, while donor shortage limits kidney transplantation—the only curative therapy. Xenogeneic regenerative medicine may overcome these challenges by generating functional kidneys

Methods

This study investigated metanephric graft development under diabetic and HIF-PHD inhibitor conditions, reflecting clinical contexts of CKD patients. Adult Lewis rats were rendered diabetic by streptozotocin (STZ) injection, and embryonic day 15 (E15) metanephroi were transplanted. Grafts were evaluated 14 days post-transplantation.

Results

In the diabetic model, graft area and glomerular number did not differ significantly from controls, suggesting preserved developmental potential. However, renal pelvic dilation was observed, indicating increased urine production.

In the HIF-PHD inhibitor (roxadustat) group, graft size was similar to controls, indicating no developmental toxicity. Notably, the number of glomeruli per unit area was significantly higher, suggesting enhanced vascular invasion and nephron formation.

Conclusion

These findings indicate that metanephric grafts can develop normally even under diabetic conditions and that HIF-PHD inhibition may further promote vascularization without adverse effects. Xenogeneic renal regeneration could thus offer a promising therapeutic option for CKD patients, many of whom have diabetes.

Kewords