Kidney Week

Abstract: FR-PO250

Turning the Kidney Into a Lymphoid Organ

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Atwood, Daniel, University of Colorado Denver School of Medicine, Aurora, Colorado, United States

Daniel Atwood,

• Oto, Ozgur Akin, Istanbul Universitesi Istanbul Tip Fakultesi, Istanbul, Istanbul, Turkey

Ozgur Akin Oto,

• Chaudhary, Anjana, University of Colorado Denver School of Medicine, Aurora, Colorado, United States

Anjana Chaudhary,

• Edelstein, Charles L., University of Colorado Denver School of Medicine, Aurora, Colorado, United States

Charles L. Edelstein,

Background

Pkd1^RC/RC mice (RC), a hypomorphic Pkd1 mouse model of ADPKD, have suppressed kidney autophagy (Atwood, Edelstein et al. Cell Signal. 2020). We hypothesized that knocking out autophagy (ATG7) in the kidney in aged mice would induce cyst growth. The first aim of the study was to breed kidney-specific autophagy knockout (ATG7-/-) mice.

Methods

ATG7-/- mice were generated using a renal tubule specific cadherin Cre-Lox system. IHC was done with the VectaStain ABC kit. Staining quantitation was done using macros on the Aperio Imagescope. TLT #, size, and index was obtained from H&E sections using an NIS Element macro.

Results

400d ATG7-/- mice had no cysts and normal kidney function. Surprisingly, large tertiary lymphoid tissues (TLT)(up to 9%) of the area of the kidney were seen in ATG7-/- kidneys. There was increased TLT size, number, and index in ATG7-/- vs. WT (Table). TLTs are ectopic lymphoid tissues composed of lymphocyte aggregates that develop de novo in nonlymphoid organs. TLTs form after tissue injury, infection, or chronic inflammation in various kidney diseases. The phenotype of TLTs in ATG7-/- was confirmed by the presence of T cell(CD3, 4, and 8), and B cell(CXCL13, CD21) markers and intense proliferation(PCNA) in the TLTs. There was also large amount of staining for pS6(mTORC1), an inducer of proliferation, in the TLTs. PKD kidneys have chronic inflammation which is known to promote the formation of TLTs. There was increased number, size, and index of TLTs in kidneys from RC mice(Table). There was intense proliferation of T cells and increased pS6 (mTORC1) staining in the TLTs in RC kidneys. Treating RC mice with the mTOR inhibitor Torin2(10 mg/kg IP) from 50-120d virtually eliminated TLTs.

Conclusion

The following novel findings are described: The presence of numerous, large and discrete TLTs in aged tubule-specific ATG7-/- kidneys, intense pS6 (mTORC1) in TLTs in ATG7-/- kidneys, first description of the presence of TLTs in PKD kidneys, and virtual elimination of TLTs by treatment of RC mice with an mTOR inhibitor. These data suggest a previously undescribed relationship between suppressed autophagy, activation of mTORC1 and the formation and growth of TLTs.

*P>0.05 **P>0.01 ***P>0.001

Funding

• Veterans Affairs Support