Chronic incubation of cultured renal tubular epithelial cells in acid medium causes an increase in Na/H antiporter activity that persists after removal from acid, is dependent on protein synthesis, and is associated with an increase in Na/H antiporter mRNA. Chronic activation of protein kinase C has similar effects in these cells. The present studies examined the role of protein kinase C in the effect of acid incubation. Incubation of MCT cells in acid for 24 h caused a 50% increase in Na/H antiporter activity. This was prevented by inhibition of protein kinase C, either with sphingosine or by protein kinase C downregulation. Pertussis toxin pretreatment did not prevent the increase in antiporter activity. Acid incubation caused an increase in transcription factor AP-1 activity, as shown by an increase in expression from a reporter gene containing six tandem AP-1 binding sites. This was associated with transient increases in c-fos and c-jun mRNAs. This response is typical of that for gene activation by protein kinase C. These studies demonstrate that acid activation of the Na/H antiporter requires protein kinase C and is associated with c-fos and c-jun expression and increased AP-1 activity.
<i>Background:</i> We previously found that the Na<sup>+</sup>/H<sup>+</sup> exchanger 3 (NHE3) is localized in the apical membrane of the rat renal proximal tubule and thick ascending limb of Henle. In the present study, we examined the direct effect of glucagon on the opossum kidney P (OKP) cell Na<sup>+</sup>/H<sup>+</sup> antiporter, encoded by NHE3. <i>Methods:</i> Na<sup>+</sup>/H<sup>+</sup> antiporter activity was measured as the rate of cell pH recovery from an acid load using 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein. Northern blot and Western blot analyses were performed using OKP NHE3 cDNA and anti-OKP-NHE3 antibodies. <i>Results:</i> Glucagon (1 ng/ml) acutely (1 h) inhibited, but chronically (24 h) activated NHE3 activity in OKP cells. These effects were blocked by either KT5720 or RpcAMP [protein kinase A (PKA) inhibitors], and mimicked by 10<sup>–4</sup><i>M</i> dibutyryl-cAMP. Both NHE3 mRNA and protein abundance increased with the 24-hour incubation in glucagon or dibutyryl-cAMP. Cycloheximide did not prevent a significant increase in NHE3 activity at 24 h. We therefore examined NHE3 protein abundance in the surface membrane by the biotinylation mehtod. cAMP or glucagon significantly increased NHE3 protein abundance in the surface membrane when incubated with cycloheximide for 24 h. <i>Conclusions:</i> Glucagon acutely inhibits but chronically activates NHE3 activity in OKP cells via a PKA-dependent pathway. Both protein-synthesis-dependent and -independent mechanisms play important roles in the chronic activation of NHE3.
This year the renal community, the United States, and the world endured two tragedies. The first of these, the events of September 11, will be remembered for many years to come. The magnitude of the devastation and pain inflicted on so many innocent people is difficult for us to grasp. Our thoughts go out to all of the victims, their loved ones, and to all of us who will live in a world that is forever changed. During the last month, the United States has experienced a level of patriotism that I have not witnessed during my lifetime. The American flag has new meaning. Singing or listening to patriotic songs, songs that we have sung our entire lives without much thought, now elicit reflection, sadness, and determination. This year we also lost a dear friend, Ramzi Cotran, one of ASN’s Past Presidents. Ramzi was on the ASN Council from 1989 to 1996 and served as its President in 1995. Ramzi was a leader among renal pathologists and was a very special person to all that knew him. I had both the honor and the pleasure of serving as Chair of the Program Committee during Ramzi’s presidency. How can one place the World Congress of Nephrology into context with the events of September 11? How does one place any event in life into perspective with the colossal events of that day? The answer is that you cannot, but yet you must. Those that planned the events of September 11 would have hoped that we would cancel this meeting. In attending the World Congress, each one of you has made a small statement that our spirit cannot be squelched. The achievements made by the participants of this Congress will continue to make the world a better place in which to live. A small minority of individuals attempts to destroy everything we create. During the next four days, we will gather to exchange information and ideas, to see old friends and colleagues, and to celebrate the successes of the national and international nephrology community. This meeting represents the first time that the American Society of Nephrology and International Society of Nephrology will meet together. Our predecessors laid the foundation for this meeting many years ago. However, when Tom Andreoli, Qais Al-Awqati, Steve Hebert and I actually started working on the meeting almost 2 years ago we found that there were a few details that were not anticipated, like the name of the meeting, the logo, whether to have an opening reception, and a long list of ASN and ISN traditions that needed to be merged together into a single meeting. Nevertheless, addressing these details has been relatively simple and enjoyable due to a true sense of collaboration that was present throughout the ISN and ASN leadership. From my point of view, I would like to say that working closely with Tom Andreoli and the International Society of Nephrology on these issues has been an exceptional pleasure. One of the key issues that was agreed upon early was that the meeting would follow a typical ASN format. While this principle was modified to accommodate a number of ISN traditions, the one principle that we held to steadfastly was to keep the registration fee low, as is typical for an ASN meeting. This was key in that it allowed many to attend this meeting who typically cannot afford to attend an international meeting. This year the chair of the program committee was Qais Al-Awqati. I first met Qais when I was an intern at Columbia Presbyterian Hospital in New York. Qais is well known for his outstanding research, but few know that he is also an unusually gifted teacher. Qais inspired many young trainees at Columbia to aspire to greatness in academics. As I planned for the ASN Presidency, one of my first decisions was to name Qais as Chair of the Program Committee. It has been a great year serving as President, but working closely with Qais again has made it special. Steve Hebert represented the ISN as the Vice Chair of the program committee. Qais and Steve together led an exceptional committee that I believe you will agree has developed a spectacular program. This committee included Sei Sasaki, Jean Pierre Grunfeld, Biff Palmer, Philip Marsden, Doris Herzlinger, Pedro Jose, Yashpal Kanwar, Eduardo Slatopolsky, Robert Safirstein, and Barbara Murphy. The committee worked hard and developed a program that combined the highest levels of science with the many traditions of the American and International Societies of Nephrology. While the Program Committee designed the scientific content of the meeting, ASN staff put their ideas into action. Melissa Reese, Director of the Annual Meeting Program, led the ASN program staff this year. While planning the ASN meeting is a difficult task in any year, developing a joint meeting between two societies with many strong traditions made this year a greater challenge. In June, Karen Campbell was hired as Executive Director of the ASN. Karen is an incredibly gifted individual with an undergraduate degree in music and mathematics, a Masters in Administrative Leadership, and a Ph.D. in Educational Administration. Her most recent position was as Vice Chair of the Department of Medicine at Georgetown University Medical Center. With Karen’s talents, she has brought the management of ASN to an entirely new level. I hope that many of you will have a chance to meet her and work with her in the future. As President I have worked closely with the ASN Council. I want to emphasize that it is this group of individuals that is responsible for most of what the society does during the year. I am not certain that many realize how hard ASN Council members work to accomplish the goals of the society. In addition, I want to thank the many members of ASN committees that contributed their time to the society this year. Many key issues are facing Nephrology today, and more will need to be addressed in the future. If the past has taught us anything, it’s that the future of medicine and nephrology is uncertain. Given this inconstant milieu, it is important that you are represented by an organization that can respond. This organization needs to have large resources; it needs to be well organized with the requisite infrastructure; it needs to be able to identify problems quickly and to be capable of responding quickly. In essence, the American Society of Nephrology has evolved into such an organization. Nevertheless, given the rate at which the issues change, ASN needs to continually transform itself. The society generates income from many different sources: the annual meeting, postgraduate education, its journal, and very generous corporate sponsors. I should emphasize that these corporate supporters generously donate large amounts of money to ASN educational programs, based on the belief that well-educated physicians benefit all who participate directly and indirectly in the care of renal patients. This year I am pleased to announce the initiation of the first endowed lectureship at the ASN meeting. As the society has matured, an increasing number of our members have achieved a level of accomplishment worthy of honoring in perpetuity. The ASN has named some of our major awards after these individuals, but the number of these awards cannot grow without limit. It was decided to institute a new mechanism for honoring these individuals, endowed lectureships. Groups of individuals or companies wishing to honor these individuals provide funds for an endowment, which then remains with the society in perpetuity. Income from the corpus provides funds for a speaker in one of the symposia or minilectures. This year is the inauguration of the Barry M. Brenner Endowed Lectureship. Funds for this were generously provided by Monarch Pharmaceuticals. Eric Neilson was selected by the program committee to present the first Barry M. Brenner lecture. He will speak on, “The Origin of the Renal Fibroblast.” Let me now describe some of the more important programs ASN is focusing on. Our government relations program is focused on a number of issues. First and foremost is increased funding for the NIH. Research funding in the United States has increased dramatically in recent years. We are in the midst of a 5-year program to double the NIH budget. The US Congress has remained committed to this increase, but the end of the 5 years is approaching. The cost of performing research has increased significantly during this time, such that doubling of the NIH budget has not resulted in a doubling of the number of funded grants. Should NIH increases decrease significantly at the end of the 5 years, or even worse before that time, research funding may suffer greatly. It is thus key that all members of the scientific community focus on keeping Congress and the President’s advisors educated with respect to the importance of medical research. Given the recent events, it is not appropriate to press Congress to fund medical research over other national priorities. Nevertheless, it is appropriate to maintain funding for medical research as a national priority. A second issue is increased funding for renal research in particular. A major role for the ASN is to make certain that kidney research receives its fair share of NIH dollars. Unfortunately, the definition of a fair share is subjective, and is dependent on the personal judgment of legislators, influenced by lobbying organizations, as well as their own personal experiences. Is renal disease more important than heart disease or lung disease? I cannot pass judgment on this, but we owe it to our patients to make certain that someone is vigorously stressing the importance of kidney disease and kidney research. The ASN has also supported a bill for GME support for underserved specialties, similar to that provided for primary care disciplines. Under this bill, if a subspecialty were designated as underserved, it would be eligible for GME support at a level similar to that provided for training in primary care. We supported this concept because of our belief that Nephrology is an underserved specialty. We also strongly supported a loan repayment program for physicians who enter a career as a physician scientist. The large loans incurred by medical students today almost eliminate the option of a career as a physician scientist, where the range of income will be lower than in private practice. Most recently, we have begun to explore with Josie Briggs and Allen Spiegel, the Director of NIDDK, the concept of a Nephrology clinical trials consortium, a group of clinical research units that could participate in multiple clinical trials. Another important issue is related to reimbursement for physician services. This is of great importance to clinicians, who comprise the majority of our membership. It has also become important to academicians, who rely on clinical income to support their budgets for teaching and research, or at least not to consume those budgets. Gone are the days when academic units can ignore the concept of an RVU. Most significantly, the rate of reimbursement is important to our patients. Students and residents choose their field of practice based on a qualitative ratio of income to working hours. While this may seem mercenary to some, it is reality. Working hours are long in Nephrology. If reimbursement is not commensurate, few will enter the field. ASN has teamed up with the Renal Physicians Association to lobby Congress on this and other issues related to the quality of clinical practice in Nephrology. This year the ASN weighed in on recertification. All agree that recertification is worthwhile, and that it is important that the public have confidence in their physicians, believing that their physicians are as or more competent than they were when they finished their training. Nevertheless, it is also important that good physicians not be subjected to an overly intrusive, demeaning, and time consuming process that serves no constructive purpose. This year I communicated with the American Board of Internal Medicine, expressing ASN’s concerns about certain components of the planned continuous professional development program. I am pleased to inform you that the ABIM has agreed to postpone initiation of the more problematic components of recertification until they can be better assessed. The ASN developed a program for awarding research grants a number of years ago. This year these programs were expanded. The Career Enhancement Grant is given to individuals who have just missed funding on their NIH grants. Eligibility criteria for this grant have been loosened so as to allow more investigators to qualify. I will discuss this grant again later in the meeting. The Gottschalk Research Scholar award is given to young investigators who have shown outstanding achievement. In collaboration with the American Society of Transplantation we have jointly funded the equivalent of a Gottschalk award committed solely to investigators working in the transplant field, the John Merrill Transplant Research Scholar award. Similarly, in collaboration with the Association of Subspecialty Professors and the Hartford Foundation, we have jointly funded an award for investigators working in geriatrics. To encourage our sister societies to participate, and to extend our funds further, we have invited these societies to join us in jointly funding more of these grant programs. To encourage medical students to choose careers in research, and specifically in renal research, we offer a grant that covers all expenses for any medical student that takes off at least 1 year from school and spends that year in the laboratory of an ASN member. We are also considering joining with NIDDK to extend their support for a loan repayment program. Our program would be aimed at physician scientists, removing one barrier toward entering such a career. It is our hope that through a well-managed investment portfolio, the generous corporate support that we receive each year, expansion of our profitable postgraduate education programs, and through more efficient management of the ASN we can increase our grant programs in the future. While it is our hope that one day ASN will have grant programs far more expansive, at present the largest quantity of funding for renal research, second to NIH, derives from the American Heart Association. This funding had been placed in jeopardy due to decreased involvement of the renal community in this organization, most evident in a declining membership. We were in danger of losing the status of a Renal Council in the AHA. This year, working with Jules Puschett, Chair of the Executive Committee of the Renal Council of the AHA, ASN decided to address this as a high priority. We have added membership in AHA to our membership form that is mailed out annually. When signing up for ASN membership, you can check a box and sign up for joint membership in the ASN and AHA. In addition, the AHA and ASN have offered a savings to you if you join both organizations. Lastly, ASN has agreed to pay for all fellows to join the AHA. The net result is that membership in the Renal Council of AHA has increased dramatically this year from approximately 630 to 1,500. I encourage all of you who are not members of the AHA to consider joining. One venture, of which the ASN is very proud, is the Journal of the American Society of Nephrology, JASN. The Journal was born under the editorial leadership of Jared Grantham, and quickly rose to attain the number one impact factor among Nephrology journals. Craig Tisher then became Editor, and brought the Journal to the next level. You will hear more about Craig later in the meeting. This year, the ASN chose Bill Couser as the next Editor of the Journal. Bill was previously a Council member and President of the ASN and has maintained a long interest in JASN. Bill has selected an outstanding editorial team. Under Bill’s leadership, the Journal will continue to seek to publish the best renal science available, both basic and clinical, and has added a new Associate Editor committed to clinical research. There will be an increased emphasis on translating science for the clinician through features such as, “This Month’s Highlights,” and more editorials. A web-based manuscript tracking system will be utilized that will allow the journal to shorten substantially the time to decision and publication. This system is on display in the JASN booth. Another area in which the ASN has been extremely active has been Postgraduate education. Bob Narins, with the help of the PGE committee organizes a board review course that is second to none. They design the Clinical Science Symposia at this meeting, which have contributed greatly to the broad attractiveness of the meeting. In addition, the committee now organizes the one- and two-day courses that comprise the first 2 days of renal week, and this year for the first time, they have organized evening symposia. It appears that the membership has an insatiable appetite for these courses. The PGE committee now offers NephSAP, the Nephrology Self-Assessment Program. Edited by Dick Glassock, this program provides bimonthly thematic reviews critiquing recent literature, with short answer questions. If answers to these questions are returned, the participant can receive Continuing Medical Education Credit. Lastly, the ASN, through its PGE committee, co-sponsors a number of meetings throughout the year, both within the United States and internationally. With the success of the PGE programs and the increase in the quality of the science presented, the ASN meeting has grown in the number of abstracts submitted and the number of attendees. The success of the PGE programs has helped to fuel a large increase in attendance by clinicians. In addition, the outstanding science has attracted many from around the globe to our meeting. We have not only maintained our position as the major Nephrology meeting in the US, but we are now the major international scientific Nephrology meeting. Approximately 50% of attendees at ASN meetings are now from outside the United States. However, this success has come with a price. The ASN meeting is no longer the intimate affair that it once was. This intimacy is sorely missed, but its loss inevitable with our success. A similar fate has befallen most of the American scientific meetings. The ASN is exploring mechanisms to bring back some of this intimacy that can be lost as attendance increases, and we welcome suggestions. This brings me to a related issue, that of the many constituencies of the ASN. As the nephrology community has grown, ASN has attracted members from varied constituencies. In many ways it has become the United Nations of Nephrology, bringing together basic researchers, clinical researchers, clinicians, pediatric nephrologists, pathologists, transplant nephrologists, dialysis-oriented nephrologists, interventional nephrologists, and other groups too numerous to name. Many of these groups have their own societies that represent their individual needs. Yet ASN continues to provide a setting where all with an interest in the kidney can meet to exchange ideas. The resources and power of the ASN provide benefits to its membership that cannot be provided by smaller societies. Each year, ASN goes to the capital with increased clout, representing a larger membership. Each year, the ASN’s resources increase, allowing it to accomplish more. As the ASN becomes a coalition of Nephrology constituencies, it is important that it represent the interests of each group well. For a time, we tried to do this by appointing Council members from the different constituencies. However, this has become difficult as the number of possible groups has increased. In addition, the democratic process that has been adopted, wherein Council members are elected by the membership, has made it difficult to elect members from smaller constituencies. It has become a more important priority that ASN represent all of its membership. How does one accomplish this? We have considered possible solutions to this dilemma at a number of strategic planning meetings. We considered forming Councils similar to NKF but were aware that this concept has not worked well. We now believe that the best approach to this is through a mixture of committees and advisory groups that assist the ASN Council by providing suggestions and by serving as a group from which the Council can seek advice. The ASN Basic Science committee was formed a number of years ago and has served this purpose well. I will speak more about this committee later in the meeting. The ASN Transplant Advisory Group has been a spectacular success. Under the leadership of Mo Sayegh, this committee has ensured that ASN Council is informed of the needs of the Transplant community. This year, we formed a Dialysis Advisory Group, which we hope will be equally successful. The key to the success of all committees is participation. We are all busy. Those who are successful have done so by not wasting time on committees that accomplish nothing. Unfortunately this becomes a circular phenomenon. If members do not participate in committees, it becomes a self-fulfilling prophecy that the committee will accomplish nothing. As ASN has grown, ASN Council no longer has the time to proactively consider all of the needs of each element of its constituency, and it is essential that these advisory groups become active, and most importantly, proactive in representing their members. I believe that in the near future the number of these advisory groups will grow, but they will only be successful if they are effective. This means that members need to do their work, and ASN Council needs to seek and heed their advice. The more effective one constituency is in attracting the resources of ASN, the more it appears that other constituencies are diminished. I can assure you that this is not true. At no point has the ASN been forced to curtail its support for one constituency so that it can increase support for another. Perhaps this point is best made by considering the two major subdivisions of the ASN community: researchers and clinicians, accepting the fact that the distinction between these groups is sometimes blurred. ASN was formed around a small nucleus of academic nephrologists. The first ASN meeting in 1967 had 1,100 attendees, all described as scientists. The meeting lasted 2 days and included plenary talks by Neal Bricker, Lou Welt, Frank Dixon, Bob Berliner, and Dan Tosteson. Eighty free communications were presented. As the society grew, its membership grew. This membership included researchers but also included practicing clinical nephrologists. In fact, it has become apparent that the majority of the membership are highly committed physicians in private practice that attend the ASN meetings to learn from the academicians. A pivotal point in the history of the ASN came when the society realized that it needed to address more directly the needs of this group. This led to the formation of what was then called the Short Courses and to the birth of the Postgraduate Education or PGE Committee. The PGE director started as a part-time position and evolved into a full-time position. In addition, the ASN joined with RPA to ensure that this element of our membership, the practitioner, was represented in our lobbying efforts and in our thoughts on public policy. Our programs to support the renal clinician have been so successful that the researchers among our membership are now expressing a concern that they have been ignored. I would like to take a few moments to make the point that this is not the case. The ASN continues to have a growing set of programs that support renal research, many of them highlighted earlier in my talk. These may appear to be have been diluted by programs to support the renal practitioner, but in fact the expanse of these programs have grown in parallel. While the PGE program has continued to thrive, the basic science and clinical science symposia continue to grow at the meeting. Each year, there are more of these symposia than in previous years. In fact the most common complaint is that there are too many good symposia, and one cannot attend all of them. ASN continues to run a Basic Science conference, and has developed a relationship with the Keystone Symposia to jointly sponsor meetings. As noted earlier, ASN’s grant program continues to grow, its support for AHA is directly for the benefit of researchers, and the majority of its lobbying efforts are related to increased funding for research. I am certain that there are more ways in which we can support our research community, and we look forward to receiving new ideas and suggestions from the Basic Science and Clinical Science Committees. The ASN Council sees both the academic and practicing communities as the heart of our society. While practicing nephrologists represent the majority of our membership, they join so they can learn from the academicians. Without the academic core of the society, there would be no PGE programs. The ASN leadership is well aware of this and is continuously seeking ways to serve all of our membership. I would like to conclude my remarks by thanking you for allowing me to serve as your President this year. It was truly an honor. There are many more business items that the ASN addressed this year, but I am reminded of a comment that Dr. Donald Seldin would typically make when he was chair of the Department of Internal Medicine at Southwestern Medical School. Dr. Seldin would typically start our weekly departmental meeting by saying something like this. “There were many problems that have arisen this week, and I have taken care of them all. Now, let’s hear a research presentation.” Thank you.
Chronic metabolic acidosis (CMA) is associated with an adaptive increase in the bicarbonate absorptive capacity of the rat medullary thick ascending limb (MTAL). To specify whether NHE-3, the apical MTAL Na/H exchanger, is involved in this adaptation, NHE-3 mRNA was quantified by a competitive RT-PCR using an internal standard which differed from the wild-type NHE-3 mRNA by an 80-bp deletion. CMA increased NHE-3 mRNA from 0.025+/-0.003 to 0.042+/-0.009 amol/ng total RNA (P < 0.005). NHE-3 transport activity was measured as the initial proton flux rate calculated from the Na-dependent cell pH recovery of Na-depleted acidified MTAL cells in the presence of 50 microM HOE694 which specifically blocks NHE-1, the basolateral MTAL NHE isoform. CMA caused a 68% increase in NHE-3 transport activity (P < 0.001). In addition, CMA was associated with a 71% increase in NHE-3 protein abundance (P < 0.05) as determined by Western blot analysis on MTAL membranes using a polyclonal antiserum directed against a cytoplasmic epitope of rat NHE-3. Thus, NHE-3 adapts to CMA in the rat MTAL via an increase in the mRNA transcript that enhances NHE-3 protein abundance and transport activity.
Incubation of opossum kidney clone P (OKP) cells in acid media (pH 6.8) causes activation of Na + /H + exchanger 3 (NHE3) at 6, 12, and 24 h. OKP cell NHE3 protein abundance was increased by 45% at 24 h of acid incubation but was unaffected at 3–12 h. By contrast, apical membrane NHE3, measured by surface biotinylation, increased approximately twofold at 6, 12, and 24 h, mirroring the increase in activity. Acid incubation caused a 76% increase in exocytic insertion of NHE3 into the apical membrane but had no effect on endocytic internalization at 6 h. Latrunculin B, an inhibitor of microfilament organization, inhibited the acid-induced increases in apical membrane NHE3, exocytic insertion of NHE3, and NHE3 activity at 6 h. These studies demonstrate two mechanisms for acid-induced increases in NHE3 activity. Beginning at 6 h, there is an increase in apical membrane NHE3 that is due to stimulated exocytic insertion and is required for increased NHE3 activity. At 24 h, there is an additional increase in total cellular NHE3.
Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ETB) receptor increases NHE3 activity. To examine the role of the ETB receptor in the response to acidosis in vivo, the present studies examined ETB receptor–deficient mice, rescued from neonatal lethality by expression of a dopamine β-hydroxylase promoter/ETB receptor transgene (Tg/Tg:ETB–/– mice). In proximal tubule suspensions from Tg/Tg:ETB+/– mice, 10–8 M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ETB–/– mice. Acid ingestion for 7 days caused a greater decrease in blood HCO3– concentration in Tg/Tg:ETB–/– mice compared with Tg/Tg:ETB+/+ and Tg/Tg:ETB+/– mice. Whereas acid ingestion increased apical membrane NHE3 by 42–46% in Tg/Tg:ETB+/+ and Tg/Tg:ETB+/– mice, it had no effect on NHE3 in Tg/Tg:ETB–/– mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ETB–/– mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ETB–/– and Tg/Tg:ETB+/+ mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ETB receptor.
Abstract The sections in this article are: Newer Techniques Carbonic Anhydrase Mechanisms of Proximal Tubular Acidification Apical Membrane Basolateral Membrane Leak Pathways Carbonic Anhydrase Summary Mechanisms of Loop of Henle Acidification Mechanisms of Distal Nephron Acidification Mechanism of Proton Secretion (Bicarbonate Absorption) Mechanism of Bicarbonate Secretion Leak Pathways Cells Mediating H + / Transport Carbonic Anhydrase Mechanisms of Regulation of Acidification Proximal Tubule Distal Tubule
