The renal collecting duct (CD), as the terminal segment of the nephron, is responsible for the final adjustments to the amount of sodium excreted in urine. While angiotensin II modulates reabsorptive functions of the CD, the contribution of these actions to physiological homeostasis is not clear. To examine this question, we generated mice with cell-specific deletion of AT1A receptors from the CD. Elimination of AT1A receptors from both principal and intercalated cells (CDKO mice) had no effect on blood pressures at baseline or during successive feeding of low- or high-salt diets. In contrast, the severity of hypertension caused by chronic infusion of angiotensin II was paradoxically exaggerated in CDKO mice compared with controls. In wild-type mice, angiotensin II induced robust expression of cyclooxygenase-2 (COX-2) in renal medulla, primarily localized to intercalated cells. Upregulation of COX-2 was diminished in CDKO mice, resulting in reduced generation of vasodilator prostanoids. This impaired expression of COX-2 has physiological consequences, since administration of a specific COX-2 inhibitor to CDKO and control mice during angiotensin II infusion equalized their blood pressures. Stimulation of COX-2 was also triggered by exposure of isolated preparations of medullary CDs to angiotensin II. Deletion of AT1A receptors from principal cells alone did not affect angiotensin II–dependent COX2 stimulation, implicating intercalated cells as the main source of COX2 in this setting. These findings suggest a novel paracrine role for the intercalated cell to attenuate the severity of hypertension. Strategies for preserving or augmenting this pathway may have value for improving the management of hypertension.
Johannes Stegbauer, Daian Chen, Marcela Herrera, Matthew A. Sparks, Ting Yang, Eva Königshausen, Susan B. Gurley, Thomas M. Coffman
The neonatal mouse kidney retains nephron progenitor cells in a nephrogenic zone for 3 days after birth. We evaluated whether de novo nephrogenesis can be induced postnatally beyond 3 days. Given the long-term implications of nephron number for kidney health, it would be useful to enhance nephrogenesis in the neonate. We induced nephron reduction by cryoinjury with or without contralateral nephrectomy during the neonatal period or after 1 week of age. There was no detectable compensatory de novo nephrogenesis, as determined by glomerular counting and lineage tracing. Contralateral nephrectomy resulted in additional adaptive healing, with little or no fibrosis, but did not also stimulate de novo nephrogenesis. In contrast, injury initiated at 1 week of age led to healing with fibrosis. Thus, despite the presence of progenitor cells and ongoing nephron maturation in the newborn mouse kidney, de novo nephrogenesis is not inducible by acute nephron reduction. This indicates that additional nephron progenitors cannot be recruited after birth despite partial renal ablation providing a reparative stimulus and suggests that nephron number in the mouse is predetermined at birth.
Florian Tögel, M. Todd Valerius, Benjamin S. Freedman, Rossella Latrino, Mor Grinstein, Joseph V. Bonventre
Craig Balmforth, Job J.M.H. van Bragt, Titia Ruijs, James R. Cameron, Robert Kimmitt, Rebecca Moorhouse, Alicja Czopek, May Khei Hu, Peter J. Gallacher, James W. Dear, Shyamanga Borooah, Iain M. MacIntyre, Tom M.C. Pearson, Laura Willox, Dinesh Talwar, Muriel Tafflet, Christophe Roubeix, Florian Sennlaub, Siddharthan Chandran, Baljean Dhillon, David J. Webb, Neeraj Dhaun
The repulsive guidance cue SLIT2 and its receptor ROBO2 are required for kidney development and podocyte foot process structure, but the SLIT2/ROBO2 signaling mechanism regulating podocyte function is not known. Here we report that a potentially novel signaling pathway consisting of SLIT/ROBO Rho GTPase activating protein 1 (SRGAP1) and nonmuscle myosin IIA (NMIIA) regulates podocyte adhesion downstream of ROBO2. We found that the myosin II regulatory light chain (MRLC), a subunit of NMIIA, interacts directly with SRGAP1 and forms a complex with ROBO2/SRGAP1/NMIIA in the presence of SLIT2. Immunostaining demonstrated that SRGAP1 is a podocyte protein and is colocalized with ROBO2 on the basal surface of podocytes. In addition, SLIT2 stimulation inhibits NMIIA activity, decreases focal adhesion formation, and reduces podocyte attachment to collagen. In vivo studies further showed that podocyte-specific knockout of
Xueping Fan, Hongying Yang, Sudhir Kumar, Kathleen E. Tumelty, Anna Pisarek-Horowitz, Hila Milo Rasouly, Richa Sharma, Stefanie Chan, Edyta Tyminski, Michael Shamashkin, Mostafa Belghasem, Joel M. Henderson, Anthony J. Coyle, David J. Salant, Stephen P. Berasi, Weining Lu
To derive new insights in diabetic complications, we integrated publicly available human protein-protein interaction (PPI) networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy. We focused on the participating proteins in the network that were computationally predicted to connect the urine metabolites.
Rintaro Saito, Anaïs Rocanin-Arjo, Young-Hyun You, Manjula Darshi, Benjamin Van Espen, Satoshi Miyamoto, Jessica Pham, Minya Pu, Simone Romoli, Loki Natarajan, Wenjun Ju, Matthias Kretzler, Robert Nelson, Keiichiro Ono, Dana Thomasova, Shrikant R. Mulay, Trey Ideker, Vivette D’Agati, Ergin Beyret, Juan Carlos Izpisua Belmonte, Hans Joachim Anders, Kumar Sharma
Diabetes is associated with altered cellular metabolism, but how altered metabolism contributes to the development of diabetic complications is unknown. We used the BKS
Kelli M. Sas, Pradeep Kayampilly, Jaeman Byun, Viji Nair, Lucy M. Hinder, Junguk Hur, Hongyu Zhang, Chengmao Lin, Nathan R. Qi, George Michailidis, Per-Henrik Groop, Robert G. Nelson, Manjula Darshi, Kumar Sharma, Jeffrey R. Schelling, John R. Sedor, Rodica Pop-Busui, Joel M. Weinberg, Scott A. Soleimanpour, Steven F. Abcouwer, Thomas W. Gardner, Charles F. Burant, Eva L. Feldman, Matthias Kretzler, Frank C. Brosius III, Subramaniam Pennathur
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates’ receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor–treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.
Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S. Waikar, Helmut Rennke, Benjamin D. Humphreys, Joseph V. Bonventre, Andreas Herrlich
Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor+ (p75NTR+) fibroblasts and homeostatic chemokine–producing fibroblasts inside TLTs, and retinoic acid–producing fibroblasts around TLTs. Deletion of CD4+ cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.
Yuki Sato, Akiko Mii, Yoko Hamazaki, Harumi Fujita, Hirosuke Nakata, Kyoko Masuda, Shingo Nishiyama, Shinsuke Shibuya, Hironori Haga, Osamu Ogawa, Akira Shimizu, Shuh Narumiya, Tsuneyasu Kaisho, Makoto Arita, Masashi Yanagisawa, Masayuki Miyasaka, Kumar Sharma, Nagahiro Minato, Hiroshi Kawamoto, Motoko Yanagita
Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl– cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI.
Orhan Efe, Janet D. Klein, Lauren M. LaRocque, Huiwen Ren, Jeff M. Sands
Vertebrate life critically depends on renal filtration and excretion of low molecular weight waste products. This process is controlled by a specialized cell-cell contact between podocyte foot processes: the slit diaphragm (SD). Using a comprehensive set of targeted KO mice of key SD molecules, we provided genetic, functional, and high-resolution ultrastructural data highlighting a concept of a flexible, dynamic, and multilayered architecture of the SD. Our data indicate that the mammalian SD is composed of NEPHRIN and NEPH1 molecules, while NEPH2 and NEPH3 do not participate in podocyte intercellular junction formation. Unexpectedly, homo- and heteromeric NEPHRIN/NEPH1 complexes are rarely observed. Instead, single NEPH1 molecules appear to form the lower part of the junction close to the glomerular basement membrane with a width of 23 nm, while single NEPHRIN molecules form an adjacent junction more apically with a width of 45 nm. In both cases, the molecules are quasiperiodically spaced 7 nm apart. These structural findings, in combination with the flexibility inherent to the repetitive Ig folds of NEPHRIN and NEPH1, indicate that the SD likely represents a highly dynamic cell-cell contact that forms an adjustable, nonclogging barrier within the renal filtration apparatus.
Florian Grahammer, Christoph Wigge, Christoph Schell, Oliver Kretz, Jaakko Patrakka, Simon Schneider, Martin Klose, Sebastian J. Arnold, Anja Habermann, Ricarda Bräuniger, Markus M. Rinschen, Linus Völker, Andreas Bregenzer, Dennis Rubbenstroth, Melanie Boerries, Dontscho Kerjaschki, Jeffrey H. Miner, Gerd Walz, Thomas Benzing, Alessia Fornoni, Achilleas S. Frangakis, Tobias B. Huber
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