Abstract
The mineralocorticoid hormone aldosterone plays a crucial role in the control of Na+ and K+ balance, blood volume, and arterial blood pressure, by acting in the aldosterone‐sensitive distal nephron (ASDN) and stimulating a complex transcriptional, translational, and cellular program. Because the complexity of the aldosterone response is still not fully appreciated, we aimed at identifying new elements in this pathway. Here, we demonstrate that the expression of the proto‐oncogene PIM3 (Proviral Integration Site of Moloney Murine Leukemia Virus 3), a serine/threonine kinase belonging to the calcium/calmodulin‐regulated group of kinases, is stimulated by aldosterone in vitro (mCCDcl1 cells), ex vivo (mouse kidney slices), and in vivo in mice. Characterizing a germline Pim3 − / − mouse model, we found that these mice have an upregulated Renin‐Angiotensin‐Aldosterone System (RAAS), with high circulating aldosterone and plasma renin activity levels on both standard or Na+‐deficient diet. Surprisingly, we did not observe any obvious salt‐losing phenotype in Pim3 KO mice as shown by normal blood pressure, plasma and urinary electrolytes, as well as unchanged expression levels of the major Na+ transport proteins. These observations suggest that the potential effects of the loss of the Pim3 gene are physiologically compensated. Indeed, the 2 other family members of the PIM kinase family, PIM1 and PIM2 are upregulated in the kidney of Pim3 − / − mice, and may therefore be involved in such compensation. In conclusion, our data demonstrate that the PIM3 kinase is a novel aldosterone‐induced protein, but its precise role in aldosterone‐dependent renal homeostasis remains to be determined.
Highlights
The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure, as evidenced by many genetic forms of human hypertension that map to the Renin-Angiotensin-Aldosterone System (RAAS) as well by the fact that blockers of this system are frequently used in the treatment of hypertension (Lifton et al 2001; Te Riet et al 2015)
PIM3 is ubiquitously expressed along the nephron It has been reported that the Pim3 mRNA is detectable in mouse total kidney (Mikkers et al 2004) and renal cell a 2019 The Authors
We found Pim3 mRNA ubiquitously expressed along the nephron, but more prominent in proximal (PCT: proximal convoluted tubule and PST: proximal straight tubule) as well as in distal (DCT, CNT, collecting duct (CCD)) tubules (Fig. 1A)
Summary
The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure, as evidenced by many genetic forms of human hypertension that map to the RAAS as well by the fact that blockers of this system are frequently used in the treatment of hypertension (Lifton et al 2001; Te Riet et al 2015). Aldosterone acts in the aldosterone-sensitive distal nephron (ASDN, composed of the late part of the distal convoluted tubule (DCT2), the connecting tubule (CNT) and the collecting duct (CD)) (Loffing et al 2001a), where it stimulates Na+ reabsorption to restore Na+ balance, blood volume, and pressure (Yagi et al 2013). At the level of an ASDN cell, aldosterone binds to the mineralocorticoid receptor (MR), and promotes its a 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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