PhD Scientific Days 2024

Molecular Medicine II.

The Role of The Myeloid Src-family Kinases in Crescentic Glomerulonephritis

Text of the abstract

Introduction: Murine nephrotoxic nephritis, a model of crescentic glomerulonephritis, involves immunization with normal sheep IgG followed by nephrotoxic serum (NTS) injection. The roles of Src-family kinases (Hck, Fgr, Lyn) are crucial in numerous disease models, yet their involvement in kidney diseases remains unclear.
Aims: We aimed to test the role of Hck, Fgr, and Lyn in the development of nephrotoxic nephritis
Methods: Gene expression changes of Src-family kinases were assessed in human lupus nephritis. Wild-type, Hck–/–Fgr–/–Lyn–/– triple knockout and Hck–/–, Fgr–/– or Lyn–/– single knockout mice were preimmunized with sheep IgG followed by intravenous injection of NTS or normal sheep serum. On the 14th day, urine was collected over a 24-hour period. After an additional day, blood was collected, the kidneys were removed, and the leukocyte infiltration and the glomerular injury were tested by flow cytometry and light microscopy.
Results: The levels of Hck, Fgr, and Lyn expression consistently rose in human lupus nephritis, unlike other Src-family kinases. Wild-type NTS-treated mice developed severe albuminuria (approx. 7 mg/day) on the fourteenth day. Crescents were present in approx. 20% of the glomeruli of these mice, with additional histological signs of glomerulosclerosis. Flow cytometric analysis has revealed massive leukocyte infiltration of the kidneys. Serum creatinine levels were two times higher in NTS-treated than in control mice. In contrast to wild-type mice, NTS-treated Hck–/–Fgr–/–Lyn–/– showed normal serum creatinine levels, dramatically reduced albuminuria, and no substantial histological abnormalities. Analysis of Hck–/–, Fgr–/– and Lyn–/– single knockouts have revealed substantial protection of Hck–/– mice from disease development, whereas the Fgr–/– and Lyn–/– are still susceptible to induction of nephrotoxic nephritis. NTS-induced albuminuria was partially reduced in chimeric mice generated by transplantation of Hck–/–Fgr–/–Lyn–/– bone marrow cells into wild-type recipients.
Conclusion: Myeloid Src-family kinases are crucial in crescentic glomerulonephritis development, likely within a radiosensitive hematopoietic compartment.
Funding: Funded by the Hungarian National Research, Development and Innovation Office (KKP-129954, TKP2021-EGA-24 and TKP2021-EGA-29) and the HUN-REN Hungarian Research Network (0207007).