Progranulin deficiency attenuates tubulointerstitial injury in a mouse unilateral ureteral obstruction model

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Progranulin (PGRN) exhibits dual roles in inflammation, acting both pro- and anti-inflammatory depending on the disease context.
• While PGRN's role in liver fibrosis is documented, its specific involvement in tubulointerstitial fibrosis requires further investigation.

Purpose of the Study:

• To investigate the role of Progranulin (PGRN) in the pathogenesis of tubulointerstitial fibrosis.
• To elucidate the impact of PGRN deficiency on kidney inflammation and fibrosis following unilateral ureteral obstruction (UUO).

Main Methods:

• Utilized Progranulin-knockout (PGRN-KO) and wild-type (WT) mice subjected to unilateral ureteral obstruction (UUO).
• Kidney tissues were analyzed histopathologically and assessed for PGRN protein expression via immunohistochemistry and Western blot.
• Quantitative PCR was employed to measure renal mRNA levels of inflammation and fibrosis markers.

Main Results:

• PGRN-KO mice exhibited significantly improved renal histology, with reduced tubular atrophy, urinary casts, and tubulointerstitial fibrosis compared to WT mice post-UUO.
• mRNA expression of key inflammation markers (Il1b, Tnf, Il6, Ccl2, Adgre1) and fibrosis markers (Tgfb1, Acta2, Fn1, Col1a2) were significantly lower in UUO-PGRN-KO mice.
• Elevated PGRN and GRN protein levels were observed in the kidneys of UUO-WT mice, correlating with increased renal inflammation and fibrosis.

Conclusions:

• Progranulin (PGRN) plays a crucial role in promoting renal inflammation and tubulointerstitial fibrosis.
• PGRN deficiency confers protection against kidney fibrosis induced by UUO.
• Elevated PGRN/GRN levels may contribute to the development of renal inflammation and fibrosis in obstructive nephropathy.