Damage Control in the Cortical Collecting Duct #expbio

Apr 04 2016 Published by under EB2016, Uncategorized

Vasopressin-Escape Does Not Involve marked Changes in the Ratio of Intercalated-to-Principal Cells in the Cortical Collecting Duct

Chou C-L, et al.

Vasopressin, also known as anti-diuretic hormone (ADH), promotes absorption of water from the kidney’s cortical collecting duct. Under certain conditions, ADH can be inappropriately secreted, resulting in excess water retention and lowering of the body’s osmolality. Changes in osmolality can be quite dangerous, especially for the brain, so it is not surprising that the collecting duct can “escape” the effect of ADH to limit low plasma sodium and osmolality. This group previously showed that such vasopressin-escape occurs in association with lowered levels of expression for aquaporin 2 (AQP2), a water channel that allows ADH to do its job.

Autocrine and paracrine regulation of collecting duct principal cell ENaC and AQP2. Much commonality exists in regulation of ENaC (left) and AQP2 (right). Flow stimulates ATP, PGE2, and ET-1, which act on their cognate receptors to inhibit Na and water reabsorption. Similarly, bradykinin, adenosine, and NE act on their receptors to inhibit ENaC and AQP2. Flow-stimulated EET uniquely inhibits Na, but not water, transport. Compared with the wide variety of inhibitors, relatively few autocrine or paracrine factors stimulate ENaC and/or AQP2 activity. Renin, ultimately via AngII, as well as PGE2 binding to EP4 receptors, are potentially capable of augmenting principal cell Na and water transport. TZDs (via PPARγ) and kallikrein (via cleavage of an autoinhibitory domain in ENaC) may increase Na reabsorption. See the text for more detailed descriptions of each regulatory factor. ACE, angiotensin-converting enzyme; AGT, angiotensinogen; Ang, angiotensin; AQP, aquaporin; EET, eicosataetranoic acid; EP, PGE receptor; ET, endothelin; NE, norepinephrine; NO, nitric oxide; PPARγ, peroxisome proliferator–activated receptor-γ; TZD, thiazolidinedione.

Autocrine and paracrine regulation of collecting duct principal cell ENaC and AQP2. Much commonality exists in regulation of ENaC (left) and AQP2 (right). Flow stimulates ATP, PGE2, and ET-1, which act on their cognate receptors to inhibit Na and water reabsorption. Similarly, bradykinin, adenosine, and NE act on their receptors to inhibit ENaC and AQP2. Flow-stimulated EET uniquely inhibits Na, but not water, transport. Compared with the wide variety of inhibitors, relatively few autocrine or paracrine factors stimulate ENaC and/or AQP2 activity. Renin, ultimately via AngII, as well as PGE2 binding to EP4 receptors, are potentially capable of augmenting principal cell Na and water transport. TZDs (via PPARγ) and kallikrein (via cleavage of an autoinhibitory domain in ENaC) may increase Na reabsorption. See the text for more detailed descriptions of each regulatory factor. ACE, angiotensin-converting enzyme; AGT, angiotensinogen; Ang, angiotensin; AQP, aquaporin; EET, eicosataetranoic acid; EP, PGE receptor; ET, endothelin; NE, norepinephrine; NO, nitric oxide; PPARγ, peroxisome proliferator–activated receptor-γ; TZD, thiazolidinedione. Click image to access full review article.

Their current question centers on how AQP2 gets down regulated. It could be an intracellular mechanism or remodeling of the collecting duct, with a change in the ratio of principal and intercalated cells in that structure. Principal cells regulate sodium, potassium, and water reabsorption in the collecting duct, while intercalated cells influence acid-base balance. Decreasing the number of principal cells could decrease the effect of ADH. A full review of principal function can be found here; the image above comes from this paper.

After micro dissecting cortical collecting duct segments from animals in the early phases of vasopressin escape, the investigators probed them with a marker for all cells; an antibody to H+-ATPase, a marker of alpha intercalated cells; and an antibody to pendrin, found in in beta intercalated cells. They could then calculate the number of principal cells and intercalated cells to see if the principal cells decreased to explain the diminished AQP2 expression.

The cellular ratios did not differ between normal and vasopressin-escape animals.

So what intracellular process could be involved? Further exploration suggests a shift in cell cycle from G0 (resting) to mitosis. How this reduces AQP2 expression is not yet clear.

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