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      In vivo Studies of the Genetically Modified Mouse Kidney

      Nephron Physiology

      S. Karger AG

      SGK1, ROMK, Mouse, Kidney, Micropuncture

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          Gene-targeted mice provide a powerful approach to study the physiological and pathophysiological role of a given protein in kidney function and can give insights on the functional importance of these proteins under in vivo conditions as well as on the potential compensating mechanisms in their absence. Full utilisation of these animal models requires adaptation of the respective methods to the size of the mouse. This applies especially to in vivo studies in mice which have to deal with rather small structures and volumes, e.g. vessels for cannulation, plasma volumes or urinary flow rates. Here some aspects which can help to study kidney function in the mouse in vivo are outlined. The applicability of these in vivo methods are stressed by reviewing their very recent application in mice being deficient for either ROMK or SGK1.

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          Most cited references 5

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          Uncompensated polyuria in a mouse model of Bartter's syndrome.

          We have used homologous recombination to disrupt the mouse gene coding for the NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick ascending limb and macula densa. This gene is one of several that when mutated causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria and electrolyte imbalance. Homozygous NKCC2-/- pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of -/- pups with indomethacin from day 1 prevented growth retardation and 10% treated for 3 weeks survived, although as adults they exhibited severe polyuria (10 ml/day), extreme hydronephrosis, low plasma potassium, high blood pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacin-rescued -/- adults except that hydronephrosis was mild. The polyuria, hypercalciuria, and proteinuria of the -/- adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant animals should be valuable for uncovering new pathophysiologic and therapeutic aspects of genetic disturbances in water and electrolyte recovery by the kidney.
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            Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome.

            ROMK is an apical K(+) channel expressed in the thick ascending limb of Henle (TALH) and throughout the distal nephron of the kidney. Null mutations in the ROMK gene cause type II Bartter's syndrome, in which abnormalities of electrolyte, acid-base, and fluid-volume homeostasis occur because of defective NaCl reabsorption in the TALH. To understand better the pathogenesis of type II Bartter's syndrome, we developed a mouse lacking ROMK and examined its phenotype. Young null mutants had hydronephrosis, were severely dehydrated, and approximately 95% died before 3 weeks of age. ROMK-deficient mice that survived beyond weaning grew to adulthood; however, they had metabolic acidosis, elevated blood concentrations of Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor urinary concentrating ability. Whole kidney glomerular filtration rate was sharply reduced, apparently as a result of hydronephrosis, and fractional excretion of electrolytes was elevated. Micropuncture analysis revealed that the single nephron glomerular filtration rate was relatively normal, absorption of NaCl in the TALH was reduced but not eliminated, and tubuloglomerular feedback was severely impaired. These data show that the loss of ROMK in the mouse causes perturbations of electrolyte, acid-base, and fluid-volume homeostasis, reduced absorption of NaCl in the TALH, and impaired tubuloglomerular feedback.
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              Absence of Small Conductance K+Channel (SK) Activity in Apical Membranes of Thick Ascending Limb and Cortical Collecting Duct in ROMK (Bartter's) Knockout Mice


                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                May 2003
                17 June 2003
                : 94
                : 1
                : p1-p5
                Department of Pharmacology, University of Tübingen, Tübingen, Germany
                71068 Nephron Physiol 2003;94:p1–p5
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 1, References: 16, Pages: 1
                Self URI (application/pdf):

                Cardiovascular Medicine, Nephrology

                Kidney, Micropuncture, Mouse, ROMK, SGK1


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