CV Science

zoubida karim Zoubida Karim, PhD Research director at CNRS

Course and current status

- PHD diploma in Pierre and Marie Curie University PARIS 6.

- 2 years Postdoctoral at Universität Zürich, Institute of Physiology, Switzerland

- National accreditation to direct Searches (HDR) in Paris Diderot University, PARIS 7.

- Current position: Researcher Director (DR2), Toulouse Institute of Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291 - CNRS UMR5051 - Toulouse III University

- Head leader of the team HIROS “Heme Iron and Oxydative Stress ROS”, until Junary 2021 in Centre de Recherche sur l’Inflammation CRI-INSERM U1149 

- Current team: https://www.infinity.inserm.fr/equipes-de-recherche-2/equipe-5-j-ausseil-r-poupot-2/

- Principal invetigator in Axe 3 (Iron metabolism and hepcidin in chronic inflammatory diseases) of the current team.

Scientific summary

Research expertise

Renal physiology, intestinal physiology, iron metabolism and transporters, heme biosynthesis

Scientific contributions

- NaCl homeostasis: The Na⁺/H⁺ (NHE) exchanger is a transporter responsible for the reabsorption of NaHCO3 and NaCl in the proximal tubule (TP) of the kidney. Several NHE forms have been identified but NHE1-3 are the best studied. Angiotensin II (AII) is the hormone that regulates NHE activity via a process involving protein kinases C (PKC). However, several expert laboratories have reported conflicting results showing that PKC can inhibit or stimulate NHE activity. Thanks to an original method of isolation and ex-vivo purified proximal tubules (PT) suspension, in 1995, I was able to explain this enigma since I demonstrated that AII exerts a biphasic effect on NHE: low doses activating only PKCz (stimulating effect of NHE3) and high doses activate PKCs a, d , and e which inhibit NHE.

- Inorganic Phosphate (Pi) balance: In the body, the Pi balance is regulated by the kidney which ensures its reabsorption by the apical cotransporter Na/Pi IIa (NaPiIIa), at the level of the PT. Confocal microscopy and structure/function analysis of the NaPiIIa transporter enabled me in 1999 to identify a PDZ motif (TRL) responsible for the targeting of NaPiIIa to the apical membrane of the PT. This identification allowed the discovery of adapter proteins (in particular NHERF1) which interact with NaPiIIa. These data were of great importance since, associated with the discovery of the three mutations of NHERF1 in patients with hypophosphatemia, they allowed me in 2008 to identify a new mechanism by which NHERF1 regulates the homeostasis of Pi. In 2000 , I studied the regulation of NaPiIIa by parathyroid hormone (PTH) and identified a KR amino acid motif responsible for the internalization and degradation of NaPiIIa by PTH. In 2004, Ito et al. showed that the PEX19 protein (involved in protein trafficking) is able to interact with the KR motif and cause the internalization of NaPi IIa by PTH.

- Acid / base balance: The Na⁺/K⁺/2Cl^- cotransporter (BSC1) of the medullary thick ascending limb of the loop of Henle (MTAL) is responsible for the reabsorption of NaCl and the excretion of the NH₄⁺ in the urine. In 2003, I showed that acidic pH increases the stability of BSC1 mRNA through motifs on its 3’-UTR. In 2009, I additionally showed that z-crystalline an mRNA-protective protein, is the primary target of acidic pH in this effect. These results highlight the crucial role of post-transcriptional control of the BSC1 gene and offer a new possibilities for molecular diagnosis of bartter syndrome.

- Hepcidin, which regulates iron homeostasis (inhibition of its absorption and its recycling by macrophages), is directly linked to anemia and hemochromatosis pathologies. It was commonly believed that hepcidin works through the interaction and degradation of ferroportin (FPN, the solely iron exporter in the body). However, in 2010, our results and those of several groups have shown that in the gut, hepcidin inhibits iron absorption without reducing the abundance of FPN. This mechanism (inhibiting the activity of FPN without an "irreversible" degradation), lead tight regulation of the intestinal iron absorption, which remains adapted to the variable physiological needs.

- In the kidney, in 2013, I demonstrated that hepcidin regulates renal iron content and revealed its protective role against urinary tract infections caused by uropathogenic E. Coli (UTI). This discovery is very important because recently, the resistance of bacteria to antibiotics has increased considerably, requiring the use of antibiotics with a wider spectrum, which is harmful for our gut microbiota. Our data suggest hepcidin as a potential therapeutic target for UTI.

- Hepcidin is upregulated by BMP6 (Bone Morphological Protein 6). In 2016, I identified the first inactivating BMP6 mutations that are responsible for impaired hepcidin production and the development of iron overload in patients.

- Because iron is inserted in the prosthetic group of heme, the metabolisms of iron and heme are closely related. In 2020, in a CEP congenital erythropoietic porphyria model, our results showed the existence of hepatic and renal iron overload due to chronic hemolysis and severe anemia. Treatment with iron chelators of CEP mice showed excellent efficacy in reducing toxic porphyrins and associated skin photosensitivity, and improving hemolytic anemia.

Current projects

My current projects remain in continuity with my previous works. They are based on coordination between fundamental and translational research with the use of animal and cellular models (secondary iron overload, inflammatory anemias, bacterial infections). The main aim of this program is to reveal the role of extrahepatic hepcidin in inflammatory and infectious pathologies and in pathologies facing oxidative stress due to the uncontrolled accumulation of iron (Sanfilippo B syndrome and neuroinflammation, rheumatoid arthritis and chronic kidney diseases).

Publications related to the works cited above::

- Protein kinase C isoforms in rat kidney proximal tubule: acute effect of angiotensin II. Am J Physiol. 1995 Jul;269:C134-40. doi: 10.1152/ajpcell.1995.269.1.C134.

- A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter.

Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12896-901. doi: 10.1073/pnas.220394197.

- NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35. doi: 10.1056/NEJMoa0802836.

- Zeta-crystallin mediates the acid pH-induced increase of BSC1 cotransporter mRNA stability. Kidney Int. 2009 Oct;76(7):730-8.doi: 10.1038/ki.2009.265.

- Intestinal DMT1 cotransporter is down-regulated by hepcidin via proteasome internalization and degradation. Gastroenterology. 2011 Apr;140(4):1261-1271.e1. doi: 10.1053/j.gastro.2010.12.037.

- Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli.  J Am Soc Nephrol. 2016 Mar;27(3):835-46. doi: 10.1681/ASN.2014101035.

- Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans. Gastroenterology. 2016 Mar;150(3):672-683.e4. doi: 10.1053/j.gastro.2015.10.049.

- Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria. Blood. 2020 Nov 19;136(21):2457-2468. doi: 10.1182/blood.2020006037.