Kidney Week

Abstract: SA-OR096

Innate Immunity Contributes to Tubular Cell Senescence in Nephronophthisis Type 7 Knockout Mouse Kidneys

Session Information

• Pathogenesis of Cystic Kidney Diseases
  November 09, 2019 | Location: 143, Walter E. Washington Convention Center
  Abstract Time: 06:06 PM - 06:18 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Liu, Dingxiao, University of Iowa, Iowa City, Iowa, United States

Dingxiao Liu,

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

Heng Jin,

• Zhang, Yan, University of Iowa, Iowa City, United States

Yan Zhang,

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

Qiong Ding,

• Rastogi, Prerna, University of Iowa, Iowa City, Iowa, United States

Prerna Rastogi,

• Igarashi, Peter, University of Minnesota, Minneapolis, Minnesota, United States

Peter Igarashi,

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

Massimo Attanasio,

Background

Nephronophthisis (NPHP), an autosomal recessive disease, is the most frequent monogenic cause of chronic renal failure during the first three decades of life. Mutations in over 25 genes have been identified as causes of this disease and in several cases, like in NPHP type 7, result in chronic DNA damage. Cell senescence is a frequent outcome of chronic DNA damage. We showed that kidney tubular cells undergo cell senescence in the Glis2 mouse model of NPHP type 7. Senescent cells secrete pro-inflammatory molecules that can induce further senescence in neighboring non-senescent cells through the activation of the Toll-like receptor/interleukin 1 receptor/NF-kB (TLR/IL-1R/NF-kB) signaling pathway. We previously reported that NF-kB is activated in kidney tubular cells of the Glis2 knockout mice. We hypothesized that inducing apoptosis of senescent cells would protect from inflammation and fibrosis, and that genetic inhibition of the TLR/IL-1R/NF-kB signaling axis would decrease tubular cell senescence in Glis2-knockout kidneys. We hypothesized that inducing apoptosis of senescent cells would protect from inflammation and fibrosis, and that genetic inhibition of the TLR/IL-1R/NF-kB signaling axis would decrease tubular cell senescence in Glis2-knockout kidneys.

Methods

To this end we used the senolytic drug FOXO4-DRI to induce apoptosis of senescent cells, and generated two mouse lines: a double knockout line lacking both Glis2 and Tlr2 in all tissues (Glis2^-/-;Tlr2^-/-); and a line in which a kidney-specific promoter (Ksp) is used to conditionally inactivate the adaptor myeloid differenziation protein 88 (MyD88) downstream of TLR/IL-1R receptors in tubular cells of Glis2-null mice (Glis2^-/-;^KspCreMyd88^f/f).

Results

We found that pharmacologic elimination of senescent cells results in reduced kidney damage, fibrosis, and apoptosis in Glis2-knockout kidneys. Noticeably, in Glis2, Tlr2 double knockouts and, to a lesser extent, in Myd88, Glis2 knockout mice senescence was reduced and tubular-cell proliferation was increased, suggesting that loss of TLR2/IL-1R activity improves the regenerative potential of tubular cells.

Conclusion

Our results further suggest that a combination of TLR/IL-1R inhibition and senolytic therapy may delay the disease progression in NPHP type 7 and other forms of this disease.

Funding

• NIDDK Support