Kidney Week

Abstract: TH-PO575

Targeting Epithelial Innate Immunity Improves Inflammation and Fibrosis in a Mouse Model of Nephronophthisis

Session Information

• Cystic Kidney Diseases - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Jin, Heng, University of Iowa, Iowa City, Iowa, United States

Heng Jin,

• Wang, Shanshan, UT Southwestern Medical Center, Dallas, Texas, United States

Shanshan Wang,

• Ding, Qiong, University of Iowa, Iowa City, Iowa, United States

Qiong Ding,

• Lu, Dongmei, UT Southwestern Medical Center, Dallas, Texas, United States

Dongmei Lu,

• Attanasio, Massimo, University of Iowa, Iowa City, Iowa, United States

Massimo Attanasio,

Background

Inactivation of the gene GLIS2 causes nephronophthisis type 7 (NPHP7), a kidney disease characterized by progressive interstitial inflammatory infiltration and fibrosis. Recently, we have shown that cell senescence of kidney epithelial cells is a central pathogenic event in this disease. Senescent cells are known to secrete an array of molecules, referred to as senescence associated secretory phenotype (SASP), that is controlled by the NF-κB pathway and sustain organ inflammation and fibrosis. Toll-like receptors (TLRs) are ‘surveillance’ receptors that recognize microbial particles and endogenous molecules. TLR2 and TLR4 are abundantly expressed on the surface of kidney epithelial cell and, when stimulated, induce activation of the NF-κB pathway through the shared adaptor myeloid differenziation protein 88 (MyD88).

Methods

We found that multiple NF-κB genes are overexpressed in Glis2 defective kidney tubular cells, including Tlr2, which is at the same time a target and an activator of NF-κB, and hypothesized that activation of epithelial innate immunity may affect inflammation and fibrosis in Glis2 knockout kidneys. We tested this hypothesis by generating Glis2^mut/mut;Tlr2^-/- and kidney epithelial specific Glis2^mut/mut;^Ksp-creMyd88^f/f double knockouts. We measured cystic area, tubular cells proliferation, apoptosis, DNA damage and senescence, interstitial inflammatory cells, fibrosis and kidney function in single and double knockout mice.

Results

No differences were detected in these parameters between Glis2^mut/mut;Tlr2^-/- and Glis2^mut/mut mice at 3, 6 and 9 months of age. On the other hand, proliferation, DNA damage, cystic index, interstitial inflammation and fibrosis was decreased in kidneys of Glis2^mut/mut;^Ksp-creMyd88^f/f, comapred to Glis2^mut/mut mice at 3 months of age. No differences of kidney function and tubular cell senescence were detected.

Conclusion

Our results indicate that epithelial innate immunity signaling concurs in maintaining inflammation and fibrosis in the mouse model of NPHP7.

Funding

• NIDDK Support