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A tribute to Rainer Friedemann Greger

2008; Elsevier BV; Volume: 74; Issue: 12 Linguagem: Inglês

10.1038/ki.2008.566

1523-1755

Florian Läng,

Rainer Friedemann Greger was born on 3 January 1946 in Regensburg, Germany. His family moved to the Lake of Constance, where he attended high school. From 1966 until 1971, he studied medicine in Munich, Germany, and Glasgow, Scotland. As a medical student, he developed a completely novel cuvette for photometry, which was later used worldwide in biochemistry and physiology departments. I was lucky enough to meet Rainer in 1966 in the first term of medical school. We studied together, attended all lectures together, sat at every single examination together, and worked together on a joint doctoral thesis dealing with the renal handling of uric acid. In the laboratory of P. Deetjen in Munich, I performed micropuncture experiments, and Rainer did the chemical analysis of renal tubular fluid. After the completion of our studies, we followed P. Deetjen to the Department of Physiology in Innsbruck. Two years later, we joined Frank Knox at the Department of Physiology and Biophysics of the Mayo Clinic in Rochester, Minnesota, to work on renal tubular transport of phosphate. In 1976, we returned to Innsbruck, where we obtained the habilitation in 1977. There, we continued to work as postdoctoral fellows side by side until 1979. By that time, we had published more than 30 joint papers on renal tubular transport of uric acid, phosphate, Ca2+, oxalate, and bicarbonate. We never argued about authorship. In 1979, Rainer joined the Department of K.J. Ullrich at the Max Planck Institute of Biophysics in Frankfurt, Germany, where Eberhard Frömter, Rolf Kinne, and Heini Murer unraveled the mechanisms of renal tubular transport. K.J. Ullrich presented him with an apparent paradox wherein Cl− seemed to be transported by an electrogenic chloride pump in the thick ascending limb, even though this nephron segment expressed abundant Na+/K+-ATPase. It was already known from studies of isolated perfused tubules that Cl transport appeared to be Na+-independent in this segment. When Rainer repeated the in vitro perfusion reported earlier by M.B. Burg and J.P. Kokko, he found that, indeed, removal of Na+ from the perfusate did not abolish the current. Rainer was, however, not satisfied with the experiment. Instead, he used pipettes made from Na+-free glass to make sure that no Na+ was leaking out from the glass, thus contaminating the perfusion fluid. The use of Na+-free solutions with Na+-free glass indeed abrogated the current.1.Greger R. Chloride reabsorption in the rabbit cortical thick ascending limb of the loop of Henle. A sodium dependent process.Pflugers Arch. 1981; 390: 38-43Crossref PubMed Scopus (100) Google Scholar Rainer thus concluded that the paradox was due to the exquisite Na+ affinity of the Na+-coupled Cl− transport, accounting for the persistence of transport in nominally Na+-free solutions. In a series of elegant experiments inspired by the observations of Hans Oberleithner and Gerhard Giebisch in the diluting segment of Amphiuma, Rainer defined the transport systems in the thick ascending limb of Henle's loop as we read it now in our textbooks: a Na+,K+,2Cl− cotransporter in parallel to a K+ channel in the luminal membrane; a Na+/K+ ATPase, Cl− channels, and a KCl cotransporter in the basolateral cell membrane; and a cation-permeable paracellular pathway allowing the passive permeation of Na+, Ca2+, and Mg2+. As he correctly concluded, the passive paracellular cation flux is driven by the lumen positive potential, generated by the luminal K+ channels and the basolateral Cl− channels.2.Greger R. Ion transport mechanisms in thick ascending limb of Henle’s loop of mammalian nephron.Physiol Rev. 1985; 65: 760-797Crossref PubMed Scopus (527) Google Scholar By patch clamping the luminal cell membranes in isolated perfused renal tubules, Rainer defined the properties of the respective K+ channels. At that time, Rainer was involved in somewhat emotional discussions with Steve Hebert, who similarly worked on the elucidation of the transport systems in the thick ascending limb. It was Steve Hebert who, years later, impressively confirmed the concept by cloning the Na+,K+,2Cl− cotransporter and the K+ channels. Later, the initially difficult relationship gave way to deep mutual respect. Presently, we do know that genetic defects of the Na+,K+,2Cl− cotransporter, of the K+ channel, or of the Cl− channels cause the various types of Bartter's syndrome. In the following years, Rainer elucidated the effect of loop diuretics and disclosed a wide variety of parameters regulating the electrolyte transport in the thick ascending limb. In 1984, Rainer visited Mount Desert Island Biological Laboratory to analyze the mechanisms of Cl− secretion in the shark rectal gland. He defined the prototypical cellular model of Cl−-secreting epithelia — that is, basolateral Na+,K+,2Cl− cotransporter in parallel to basolateral K+ channels and Na+/K+-ATPase, as well as luminal Cl− channels. Again, Na+ permeates through the paracellular pathway. The paracellular Na+ transport into the lumen of Cl−-secreting epithelia is driven by the lumen negative transepithelial potential difference, which is generated by the luminal Cl− channels and the basolateral K+ channels.3.Greger R. Schlatter E. Mechanism of NaCl secretion in the rectal gland of spiny dogfish (Squalus acanthias). I. Experiments in isolated in vitro perfused rectal gland tubules.Pflugers Arch. 1984; 402: 63-75Crossref PubMed Scopus (94) Google Scholar,4.Greger R. Schlatter E. Mechanism of NaCl secretion in rectal gland tubules of spiny dogfish (Squalus acanthias). II. Effects of inhibitors.Pflugers Arch. 1984; 402: 364-375Crossref PubMed Scopus (65) Google Scholar,5.Greger R. Schlatter E. Wang F. Forrest Jr, J.N. Mechanism of NaCl secretion in rectal gland tubules of spiny dogfish (Squalus acanthias). III. Effects of stimulation of secretion by cyclic AMP.Pflugers Arch. 1984; 402: 376-384Crossref PubMed Scopus (96) Google Scholar Together with his colleagues and friends from Hoechst, including H.J. Lang, H.C. Englert, M. Hropot, and H. Gögelein, he developed novel Cl− channel blockers, including the nowadays widely used NPPB. Moreover, Rainer became interested in the mechanisms underlying cystic fibrosis, a relatively common, devastating genetic disease caused primarily by defective Cl− secretion. In addition to identifying the mechanisms of transport in the thick ascending limb and Cl−-secreting epithelia, Rainer studied transport in a wide variety of epithelia from the kidney, gastrointestinal tract, and inner ear. He published almost 300 scientific papers, most of them dealing with epithelial transport. Whatever Rainer did, he illuminated that scientific field with his sharp mind and unmatched experimental brilliance. Remarkably, Rainer's right eye was almost blind, and everyone would have predicted that the absence of binocular vision would prevent him from learning difficult techniques, such as micropuncture, perfusion of isolated renal tubules, or patch clamping. It is well known that he became one of the most brilliant experimentalists using each of these techniques. I have never known anyone who was a more dedicated and skilled experimenter than Rainer. If scientific discussions at meetings led to equivocal results and beliefs, he would hasten to do the appropriate experiments upon his return from the meeting in attempts to replace theory with knowledge. In 1986, Rainer was offered the chairmanship of the Physiology Department at the University of Freiburg. He made this department one of the leading research and educational institutions in Germany. He soon was appointed dean of the faculty. He organized several scientific meetings, including the annual meeting of the German Physiological Society and the German Society of Nephrology. From 1997 onward, he was a council member of the International Union of Physiological Sciences. For his scientific achievements, Rainer received a number of prestigious honors, including the Anton von Eiselsberg Prize of the Austrian Medical Association, the Friedrich Gustav Jakob Henle Medal of the University of Göttingen, the Volhard Prize of the German Society of Nephrology, the Adolf Fick Prize of the German Physiological Society, and the Leibniz Prize, the most prestigious scientific prize in Germany. As a student, he was admitted to the Studienstiftung des Deutschen Volkes, a foundation supporting the top 1% of the students in Germany, and later he was elected as a member of the German Academy of Sciences Leopoldina and of the Academy of Sciences, Heidelberg. Under Rainer’s guidance, an impressive number of his young fellows became excellent scientists, including E. Schlatter, M. Wittner, A. DiStefano, P. Wangemann, K. Kunzelmann, I. Novak, H. Pavenstädt, M. Bleich, R. Nitschke, E. Lohrmann, R. Warth, J. Leipziger, R. Kubitz, J. Hirsch, S. Dijkstra, M. Köttgen, M.J. Hug, G. Kerst, M. Mall, D. Ecke, R. Schreiber, I.E. Thiele, D. Heitzmann, A. Zdebik, S. Ullrich, and H. Velzquez. In 1997, Rainer asked me whether I would like to join him in Mount Desert Island laboratories to work together as in our earlier times. I enthusiastically agreed, and we wrote a project for the Deutsche Forschungsgemeinschaft. The summer of 1997 was a wonderful time of exciting experiments and fascinating discussions. We did not know, though, that this would be our last summer working together. On 5 July 1999, Rainer left the department by bicycle, even though the weather forecast predicted a thunderstorm. During his ride, Rainer was struck by lightning. Cardiac fibrillation caused cerebral ischemia, and he never recovered from this severe accident. On 16 December 2007, he died in Heitersheim, his hometown, close to Freiburg. In the years between Rainer’s accident and his death, Rainer was cared for by his admirable wife Beate, and supported by their three children, Vinzenz, Walter, and Veronika. They have our deepest respect and sympathy. Rainer’s scientific achievements have become historic in biomedicine. Beyond that, the memory of his outstanding personality will remain deeply etched in our hearts and minds.