Jan. 28, 2009 In a study funded by the Dutch Kidney Foundation (DKF) a research group at Radboud University Nijmegen Medical Centre in the Netherlands, found that stem cells and ABC transporter proteins are indispensable for tubular regeneration after acute kidney injury.
Said project leader Dr. Rosalinde Masereeuw: 'To our surprise, our knockout mice for the ABC transporters P-gp and BCRP, P-gycoprotein and breast cancer resistance protein, were protected against acute kidney damage. This was the opposite of what we expected since the transporters usually have a protective function in excreting potentially toxic compounds, while these mice lack expression. Moreover, when we cross transplanted bone marrow between normal mice and the knockouts it turned out that bone marrow from the knockouts was the source of protection.'
Acute kidney injury is an important cause for the need of acute hemodialysis and a source of kidney failure. On the other hand, the kidney has a remarkable capacity for recovery. Stem cells seemed to have a limited share in the repair process, but now this study suggests otherwise.
'It was known that stem cells from the bone marrow express P-gp and BCRP abundantly but will downregulate them at differentiation. Repair of tubular damage in the kidney depends primarily on local cells but stem cells are involved as well. Further, we observed an upregulation in the expression of the transporters during ischemic injury. .So we thought they might be important in renal regeneration.'
ABC transporters (ATP binding cassette transporters) form a superfamily of highly conserved transporter proteins whose functions are not yet well understood. However, BCRP and especially P-gp have been studied in more detail in man. These cell membrane pumps are responsible for the transport of many substances, for instance drug molecules in the intestine. P-gp plays an important role in drug resistance of tumour cells.
Masereeuw: 'Our new hypothesis claims a bigger role for bone marrow derived stem cells in kidney regeneration. A possible mechanism is the infiltration of macrophages. These large immune cells have subgroups one of which increases damage but another supports tissue regeneration.'
Also, the study showed that mice without P-gp expression lose renal tubular function in a way comparable to Fanconi syndrome in man. BCRP knockouts, on the other hand, have a normal kidney function.
Blocking P-gp and BCRP
There is a great need for novel therapies that limit kidney damage after acute injury by toxic substances or shortage of oxygen, as in transplant kidneys which have no blood supply during transport. The results from this DKF study are pointing at inhibition of the transporters in kidney or bone marrow to strengthen the regenerative power of stem cells.
'Next, we will try to discover the mechanism by which stem cells and ABC transporters contribute to kidney repair', concludes Dr. Masereeuw, 'and we will test the effect of transporter blockers in our mouse models. We are convinced there are good opportunities here for new drug targets.'
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- Huls et al. The Role of ATP Binding Cassette Transporters in Tissue Defense and Organ Regeneration. Journal of Pharmacology and Experimental Therapeutics, 2008; 328 (1): 3 DOI: 10.1124/jpet.107.132225
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