Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin

Cyclosporin A (CsA), a widely used immunosuppressant, causes distal renal tubular acidosis (dRTA). It exerts its immunosuppressive effect by a calcineurin-inhibitory complex with its cytosolic receptor, cyclophilin A. However, CsA also inhibits the peptidyl prolyl cis-trans isomerase (PPIase) activity of cyclophilin A. We studied HCO3− transport and changes in β-intercalated cell pH on luminal Cl− removal in isolated, perfused rabbit cortical collecting tubules (CCDs) before and after exposure to media pH 6.8 for 3 h. Acid incubation causes adaptive changes in β-intercalated cells by extracellular deposition of hensin ( J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO3− secretory flux, estimated as the difference between net flux and that after Cl− removal from the lumen, was −6.7 ± 0.2 pmol·min−1·mm−1 and decreased to −1.3 ± 0.2 after acid incubation. CsA in the bath prevented the adaptive decreases in HCO3− secretion and apical Cl−:HCO3− exchange. To determine the mechanism, we incubated CCDs with FK-506, which inhibits calcineurin activity independently of the host cell cyclophilin. FK-506 did not prevent the acid-induced adaptive decrease in unidirectional HCO3− secretion. However, [AD-Ser]8 CsA, a CsA derivative, which does not inhibit calcineurin but inhibits PPIase activity of cyclophilin A, completely blocked the effect of acid incubation on apical Cl−:HCO3− exchange. Acid incubation resulted in prominent “clumpy” staining of extracellular hensin and diminished apical surface of β-intercalated cells [smaller peanut agglutinin (PNA) caps]. CsA and [AD-Ser]8 CsA prevented most hensin staining and the reduction of apical surface; PNA caps were more prominent. We suggest that hensin polymerization around adapting β-intercalated cells requires the PPIase activity of cyclophilins. Thus CsA is able to prevent this adaptation by inhibition of a peptidyl prolyl cis-trans isomerase activity. Such inhibition may cause dRTA during acid loading.

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Faculty Opinions recommendation of Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10733958.11626057 ◽

2011 ◽

Author(s):

Christie Thomas

Keyword(s):

Renal Tubular Acidosis ◽

Distal Renal Tubular Acidosis ◽

Intercalated Cells ◽

Renal Tubular

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Deletion of hensin/DMBT1 blocks conversion of - to -intercalated cells and induces distal renal tubular acidosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1010364107 ◽

2010 ◽

Vol 107 (50) ◽

pp. 21872-21877 ◽

Cited By ~ 57

Author(s):

X. Gao ◽

D. Eladari ◽

F. Leviel ◽

B. Y. Tew ◽

C. Miro-Julia ◽

...

Keyword(s):

Renal Tubular Acidosis ◽

Distal Renal Tubular Acidosis ◽

Intercalated Cells ◽

Renal Tubular

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Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis.

Journal of the American Society of Nephrology ◽

10.1681/asn.v871109 ◽

1997 ◽

Vol 8 (7) ◽

pp. 1109-1117

Author(s):

B Bastani ◽

D Underhill ◽

N Chu ◽

R D Nelson ◽

L Haragsim ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Tubular Acidosis ◽

Frozen Section ◽

Collecting Duct ◽

Rat Kidney ◽

Distal Renal Tubular Acidosis ◽

Intercalated Cells ◽

Urine Ph ◽

Control Serum ◽

Renal Tubular

In patients with Sjögren's syndrome and a secretory-defect distal renal tubular acidosis (dRTA), absence of vacuolar H(+)-ATPase from collecting duct intercalated cells has been reported. The H(+)-ATPase was examined in two patients with lupus nephritis and hyperkalemic (presumed voltage defect) dRTA. Both patients had a positive urine anion gap, alkaline urine despite acidemia, no rise in urine PCO2 with alkaluria, a urine pH > 5.5, and urine potassium excretion rate not significantly increased after 80 mg of intravenous furosemide. In both patients, immunocytochemistry of renal biopsy frozen sections with an anti-H(+)-ATPase monoclonal antibody showed bright staining of the proximal tubule brush border and collecting duct intercalated cells. In one patient, routine immunofluorescence analysis of a frozen section of her kidney biopsy with antihuman IgG showed staining of the collecting duct, indicative of autoantibodies to this segment. Moreover, rat kidney sections incubated with her serum showed labeling of the intercalated cells. On immunoblots of human kidney microsomal membranes performed with serum from both patients, an immunoreactive polypeptide was observed at M(r) approximately 56 kD that was not seen with control serum. Neither patient's sera reacted with affinity-purified bovine H(+)-ATPase or with lysates from 293 cell fibroblasts in which either of both isoforms of the human H(+)-ATPase B subunit (56 kD) were expressed. These findings demonstrate that the spectrum of dRTA includes the preservation of H(+)-ATPase in intercalated cells, in patients with presumed voltage defect dRTA. Moreover, some patients may have autoantibodies to the intercalated cells that are not directed to subunits of the H(+)-ATPase.

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Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.

Journal of the American Society of Nephrology ◽

10.1681/asn.v62295 ◽

1995 ◽

Vol 6 (2) ◽

pp. 295-301

Author(s):

P E DeFranco ◽

L Haragsim ◽

P G Schmitz ◽

B Bastani

Keyword(s):

Renal Biopsy ◽

Renal Tubular Acidosis ◽

Collecting Duct ◽

Band 3 ◽

Distal Renal Tubular Acidosis ◽

Hydrogen Ion ◽

Intercalated Cells ◽

Band 3 Protein ◽

Ion Secretion ◽

Renal Tubular

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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Correction for Gao et al., Deletion of hensin/DMBT1 blocks conversion of - to -intercalated cells and induces distal renal tubular acidosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1217165109 ◽

2012 ◽

Vol 109 (45) ◽

pp. 18625-18625

Keyword(s):

Renal Tubular Acidosis ◽

Distal Renal Tubular Acidosis ◽

Intercalated Cells ◽

Renal Tubular

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Gut It Out: Laxative Abuse Mimicking Distal Renal Tubular Acidosis

Kidney & Blood Pressure Research ◽

10.1159/000501855 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1294-1299 ◽

Cited By ~ 2

Author(s):

Marius Sidler ◽

Nilufar Mohebbi ◽

Ewout J. Hoorn ◽

Carsten A. Wagner

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Kidney Stones ◽

Relative Number ◽

Potassium Citrate ◽

Distal Renal Tubular Acidosis ◽

Anion Gap ◽

Intercalated Cells ◽

Laxative Abuse ◽

Renal Tubular

Background: Distal renal tubular acidosis (dRTA) can be inherited or acquired. Case Presentation: Here, we describe the case of a 45-year-old female patient with non-anion gap metabolic acidosis, hypokalemia, and alkaline urine. She had a history of rheumatoid arthritis and kidney stones and failed to acidify urine upon the fludrocortisone and furosemide test. Therefore, the diagnosis of dRTA secondary to an autoimmune disease was made. A kidney biopsy was examined for markers of acid-secretory intercalated cells. Surprisingly, no obvious difference in the relative number of acid-secretory intercalated cells or in the distribution of major proteins involved in acid secretion was found. Furthermore, increasing doses of potassium citrate failed to correct the hypokalemia and acidosis. Since these findings were rather atypical for autoimmune dRTA, alternative causes of her hypokalemia and metabolic acidosis were sought. The patient was found to chronically consume laxatives, which can also cause kidney stones and may result in a false-positive urinary acidification test. Conclusion: Chronic laxative abuse may mimic dRTA and should therefore be considered in unexplained hypokalemia with non-anion gap metabolic acidosis.

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Inherited Proximal and Distal Renal Tubular Acidosis

10.2310/nephro.12046 ◽

2017 ◽

Author(s):

Patricia Valles ◽

Jesus Moran-Farias ◽

Daniel Batlle

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Distal Renal Tubular Acidosis ◽

Anion Gap ◽

Intercalated Cells ◽

Acid Excretion ◽

Acid Base ◽

Urine Ph ◽

Renal Tubular ◽

Net Acid Excretion

Acid-base homeostasis by the kidney is maintained through proximal tubular reclamation of filtered bicarbonate and the excretion of the daily acid load by collecting duct type A intercalated cells. The impairment of either process results in renal tubular acidosis (RTA), a group of disorders characterized by a reduced net acid excretion and a persistent hyperchloremic, non–anion gap metabolic acidosis. The primary or hereditary forms of proximal (pRTA) and distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in either reduced bicarbonate reabsorption or reduced H+ secretion and impaired acid excretion. dRTA is characterized by reduced net acid excretion and an inability to lower urine pH despite severe acidemia (but minimal HCO3– wastage). pRTA (type 2), by contrast, is characterized by marked HCO3– wastage but preserved ability to lower urine pH when plasma HCO3– (and therefore filtered HCO3–) is below a certain threshold. In children with dRTA, growth retardation caused by chronic metabolic acidosis is the key manifestation but is fully reversible with appropriate alkali therapy if initiated early in life. A striking manifestation of many patients with dRTA is the development of severe hypokalemia that may cause muscle paralysis. In this review, we discuss these types of hereditary RTA and the mechanisms involved in the genesis of these inherited tubular disorders. This review contains 5 figures, 1 table, and 103 references. Key words: Proximal renal tubular acidosis (pRTA), Distal renal tubular acidosis (dRTA), Hyperchloremic, non–anion gap metabolic acidosis, Hypokalemia, Fractional HCO3– excretion, Urinary gap, Fanconi Syndrome.ATP6V1B1 and ATP6V0A4 gene mutations . Intercalated cells ,

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Nitric Oxide Production Modulates Cyclosporin A-Induced Distal Renal Tubular Acidosis in the Rat

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.102.048207 ◽

2003 ◽

Vol 305 (3) ◽

pp. 840-845 ◽

Cited By ~ 17

Author(s):

Shuichi Tsuruoka ◽

George J. Schwartz ◽

Michi Wakaumi ◽

Kenta Nishiki ◽

Hisashi Yamamoto ◽

...

Keyword(s):

Nitric Oxide ◽

Cyclosporin A ◽

Renal Tubular Acidosis ◽

Distal Renal Tubular Acidosis ◽

Nitric Oxide Production ◽

Oxide Production ◽

Renal Tubular

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Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis.

Journal of the American Society of Nephrology ◽

10.1681/asn.v32264 ◽

1992 ◽

Vol 3 (2) ◽

pp. 264-271

Author(s):

E P Cohen ◽

B Bastani ◽

M R Cohen ◽

S Kolner ◽

P Hemken ◽

...

Keyword(s):

Proximal Tubule ◽

Renal Tubular Acidosis ◽

Brush Border ◽

Human Kidney ◽

Sjogren's Syndrome ◽

Distal Renal Tubular Acidosis ◽

Intercalated Cells ◽

Normal Human Kidney ◽

Normal Human ◽

Renal Tubular

Distal urinary acidification abnormalities may arise from transepithelial voltage defects, permeability defects, or proton-secretory defects, but tests to determine the cellular mechanisms underlying secretory abnormalities have not previously been reported. A patient with Sjogren's syndrome and distal renal tubular acidosis due to a secretory defect is described, whose kidney biopsy was examined by fluorescent immunocytochemistry with an antibody to the M(r) 31,000 subunit of the mammalian kidney vacuolar H(+)-ATPase and was compared with normal human kidney. Staining with the anti-H(+)-ATPase antibody in normal human kidney was detected in the brush border microvilli and subvillar invaginations of the proximal tubule and in intercalated cells in the collecting duct. A biopsy sample from the patient was devoid of any anti-H+-ATPase staining in the intercalated cells. Staining was also absent from the proximal tubule brush border microvilli but was present in the subvillar invaginations. Although autoantibodies to normal human kidney membrane proteins were detected in the serum by immunoblot analysis, no immunocytochemical evidence for anti-intercalated cell autoantibodies was observed in the patient's serum. This report demonstrates that the basis for the proton secretory defect in some patients with distal renal tubular acidosis is likely the absence of H(+)-ATPase in the intercalated cells. It also illustrates the potential diagnostic utility of anti-H(+)-ATPase antibodies in the classification of distal renal tubular acidoses.

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