Kidney Week

Abstract: SA-PO528

Chloride Channel Accessory 1 (CLCA1)-TMEM16A-Chloride Current Axis: A Novel Kidney Injury Pathway in Aging and Diabetes

Session Information

• Diabetic Kidney Disease: Basic - III
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Lee, Hak Joo, University of Texas Health San Antonio, San Antonio, Texas, United States

Hak Joo Lee,

• Sun, Yuyang, University of Texas Health San Antonio, San Antonio, Texas, United States

Yuyang Sun,

• Donati, Andrew, University of Texas Health San Antonio, San Antonio, Texas, United States

Andrew Donati,

• Kevil, Christopher G., LSU Health Shreveport, Shreveport, Louisiana, United States

Christopher G. Kevil,

• Salmon, Adam, University of Texas Health San Antonio, San Antonio, Texas, United States

Adam Salmon,

• Madesh, Muniswamy, University of Texas Health San Antonio, San Antonio, Texas, United States

Muniswamy Madesh,

• Ghosh-Choudhury, Goutam, University of Texas Health San Antonio, San Antonio, Texas, United States

Goutam Ghosh-Choudhury,

• Singh, Brij, University of Texas Health San Antonio, San Antonio, Texas, United States

Brij Singh,

• Sharma, Kumar, University of Texas Health San Antonio, San Antonio, Texas, United States

Kumar Sharma,

• Kasinath, Balakuntalam S., University of Texas Health San Antonio, San Antonio, Texas, United States

Balakuntalam S. Kasinath,

Background

CLCA1 activates TMEM16A, a Ca⁺⁺-dependent chloride channel. RNA Seq showed increased expression of CLCA1 in renal cortex of old vs. young mice. We have reported that renal changes in aging and diabetes are associated with deficient generation of hydrogen sulfide (H₂S) (Lee, 2012, Lee, 2018). We studied role of CLCA1 in kidney injury in aging and diabetes.

Methods

We employed young and aging mice (n=10 per group). We also studied aging mice treated with (n=20) or without sodium hydrosulfide (NaHS) (n=14), a source of H₂S. Diabetic db/db mice with littermate controls (n=3 per group) were studied after being treated with or without NaHS. We overexpressed human CLCA1 (hCLCA1) in proximal tubular epithelial MCT cells.

Results

In aging mice renal CLCA1 expression was increased but not TMEM16A in association with mTORC1 activation, senescence associated secretory phenotype (SASP, consisting of increase in p53, p21, p16, IL-1and IL-6), albuminuria and fibrosis; all these were ameliorated by NaHS administration. Overexpression of hCLCA1 in MCT cells resulted in increase in chloride current by patch clamp, mTORC1 activation, induction of SASP and increase in matrix protein fibronectin. TMEM16A inhibitor and NaHS individually abolished these changes. In diabetic mice renal cortical expression of CLCA1 and TMEM16A was increased in association with mTORC1 activation, SASP, albuminuria, and matrix increase; these changes were ameliorated by NaHS. In MCT cells, high glucose augmented renal cortical expression of CLCA1 and TMEM16A. siRNA against CLCA1 and TMEM16A individually abolished high glucose-induced fibronectin and collagen 1 protein increase. Patch clamp showed high glucose increased chloride current that was abolished by NaHS and TMEM16A inhibitor.

Conclusion

Renal cortical H₂S deficiency in aging and diabetes is associated with increased CLCA1 expression; it is ameliorated by H₂S administration. Overexpression of hCLCA1 activates chloride current, mTORC1, induces SASP and matrix protein increase in renal cells. High glucose induced mTORC1 and matrix increase requires activation of CLCA1-TMEM16A-chloride current. These data suggest that CLCA1-TMEM16A-chloride current pathway is a novel contributor to kidney injury in aging and diabetes.

Funding

• Veterans Affairs Support