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Renal Salt and Water Homeostasis: a New Regulatory Pathway Involving the Ser/Thr Kinase PIM‐3
Author(s) -
Spirli Alessia,
Ronzaud Caroline,
Debonneville Anne,
Staub Olivier
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.963.1
Subject(s) - aldosterone , homeostasis , sgk1 , kinase , endocrinology , biology , medicine , nephron , kidney , microbiology and biotechnology
Since many years now, scientists believe that a great credit for the blood pressure regulation goes to the kidneys, as their inability in maintaining salt balance and water homeostasis can result in the development of hypertension, the most common disease in the human population. Aldosterone is the key hormone in the control of sodium balance, blood volume and blood pressure, acting in the aldosterone‐sensitive distal nephron (ASDN) and stimulating a complex transcriptional, translational and cellular program. We have carried out a gene expression profiling in a mouse cortical collecting duct cell model (mpkCCD), stimulated or not by aldosterone and identified the PIM‐3 Ser/Thr kinase as a novel aldosterone‐induced protein. PIM kinases (PIM‐1, ‐2 and ‐3), and in particular PIM‐3, are overexpressed in different tumors and are known to be regulators of apoptosis, cell proliferation and cell metabolism. PIM‐3, the PIM kinase family member most expressed in the kidney, has similar substrate specificities to other Ser/Thr kinases (e.g. SGK1, PKB), and despite its circadian expression in several organs including the kidney, its renal role is largely unknown. Here we studied a possible new role of PIM‐3 in the regulation of renal salt and water handling, both in vitro (mCCD cl1 cells) and in vivo (PIM‐3 KO mice). In mCCD cells, we confirmed that PIM‐3 expression is stimulated by aldosterone in a dose dependent manner and observed that shRNA‐based suppression of PIM‐3 reduces the aldosterone‐mediated sodium currents as well as the activation of the aldosterone‐mineralocorticoid receptor pathway. In PIM‐3 KO mice, we found decreased body weight, increased circulating renin activity and elevated plasma aldosterone levels compared to control littermates. Moreover, challenging WT and KO mice with standard, low Na + or high‐Na + diet, we observed a tendency of impaired expression of the most important electrolytes transporters in case of PIM‐3 deficiency, leading to a different sodium and water handling between WT and KO mice. In conclusion, our data suggest a possible novel function of the PIM‐3 kinase and its potentially important role in the control of sodium and water homeostasis to finely regulate blood pressure.