This proposal will investigate the role of small non-coding RNAs, termed microRNAs (miRs), in the regulation of sodium (Na+) transport in the distal kidney nephron. We will investigate the hypothesis that the mineralocorticoid hormone, aldosterone regulates the expression of specific miR clusters in the distal kidney nephron cortical collecting duct (CCD), to alter Na+ transport by targeting the expression of the scaffold protein intersectin-2. Using in vivo mouse models we will establish the regulation of miRs in the principal cells of the CCD. The significantly regulated miRs that are altered by aldosterone and other signaling pathways linked to sodium regulation will be determined. We will alter the expression of the miR-23~24~27 clusters to demonstrate its importance in maintaining sodium balance in the kidney. Finally the mechanism of intersectin-2 regulation of the epithelial sodium channel will be determined, to characterize the involvement of this novel aldosterone-repressed protein in Na+ regulation in the kidney.

Public Health Relevance

This proposal will investigate the role of small non-coding RNAs, termed microRNAs (miRs), in the regulation of sodium (Na+) transport in the distal kidney nephron. We will investigate the hypothesis that the mineralocorticoid hormone, aldosterone regulates the expression of specific miR clusters in the distal kidney nephron cortical collecting duct (CCD), to alter Na+ transport by targeting the expression of the scaffold protein intersectin-2. Using in vivo mouse models we will establish the regulation of miRs in the principal cells of the CCD. The significantly regulated miRs that are altered by aldosterone and other signaling pathways linked to sodium regulation will be determined. We hypothesize that different signaling cascades may regulate miRs differently to produce a miR signature so that a unique signaling response can be elicited for each. We will alter the expression of the miR-23~24~27 clusters to demonstrate its importance in maintaining sodium balance in the kidney. Finally the mechanism of intersectin-2 regulation of the epithelial sodium channel will be determined, to characterize the involvement of this novel aldosterone-repressed protein in Na+ regulation in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK102843-05
Application #
9695201
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Ketchum, Christian J
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Espiritu, Eugenel B; Crunk, Amanda E; Bais, Abha et al. (2018) The Lhx1-Ldb1 complex interacts with Furry to regulate microRNA expression during pronephric kidney development. Sci Rep 8:16029
Butterworth, Michael B (2018) The tale of two (distal nephron) cell types. Am J Physiol Renal Physiol 314:F930-F931
Butterworth, Michael B (2018) Role of microRNAs in aldosterone signaling. Curr Opin Nephrol Hypertens 27:390-394
Liu, Xiaoning; Edinger, Robert S; Klemens, Christine A et al. (2017) A MicroRNA Cluster miR-23-24-27 Is Upregulated by Aldosterone in the Distal Kidney Nephron Where it Alters Sodium Transport. J Cell Physiol 232:1306-1317
Klemens, Christine A; Edinger, Robert S; Kightlinger, Lindsay et al. (2017) Ankyrin G Expression Regulates Apical Delivery of the Epithelial Sodium Channel (ENaC). J Biol Chem 292:375-385
Mukherjee, Anindit; Wang, Zhijian; Kinlough, Carol L et al. (2017) Specific Palmitoyltransferases Associate with and Activate the Epithelial Sodium Channel. J Biol Chem 292:4152-4163
Li, Yue; Hu, Hongxiang; Butterworth, Michael B et al. (2016) Expression of a Diverse Array of Ca2+-Activated K+ Channels (SK1/3, IK1, BK) that Functionally Couple to the Mechanosensitive TRPV4 Channel in the Collecting Duct System of Kidney. PLoS One 11:e0155006