A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Hayek, Salim S; Koh, Kwi Hye; Grams, Morgan E; Wei, Changli; Ko, Yi-An; Li, Jing Jing; Samelko, Beata; Lee, Hyun Kun; Dande, Ranadheer R.; Lee, Ha Won; Hahm, Eunsil; Peev, Vasil; Tracy, Melissa; Tardi, Nicholas J; Gupta, Vineet; Altintas, Mehmet M.; Garborcauskas, Garrett; Stojanović, Nikolina; Winkler, Cheryl A.; Lipkowitz, Michael S.; Tin, Adrienne; Inker, Lesley A.; Levey, Andrew S; Zeier, Martin; Freedman, Barry I.; Kopp, Jeffrey B; Skorecki, Karl; Coresh, Josef; Quyyumi, Arshed A.; Sever, Sanja; Reiser, Jochen

doi:10.1038/nm.4362

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A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Author(s): Salim S Hayek , Kwi Hye Koh , Morgan E Grams , Changli Wei , Yi-An Ko , Jing Li , Beata Samelko , Hyun Lee , Ranadheer R Dande , Ha Won Lee , Eunsil Hahm , Vasil Peev , Melissa Tracy , Nicholas J Tardi , Vineet Gupta , Mehmet M Altintas , Garrett Garborcauskas , Nikolina Stojanovic , Cheryl A Winkler , Michael S Lipkowitz , Adrienne Tin , Lesley A Inker , Andrew S Levey , Martin Zeier , Barry I Freedman , Jeffrey B Kopp , Karl Skorecki , Josef Coresh , Arshed A Quyyumi , Sanja Sever , Jochen Reiser

Publication date Created: June 26 2017

Publication date (Print): June 26 2017

Journal: Nature Medicine

Publisher: Springer Nature

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Abstract

A complex of suPAR and high-risk variants of APOL1 acting on integrin signaling in the kidney contributes to APOL1-associated chronic kidney disease.

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Most cited references 33

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APOL1 risk variants, race, and progression of chronic kidney disease.

Afshin Parsa, W.H. Linda Kao, Dawei Xie … (2013)

Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

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Modification of kidney barrier function by the urokinase receptor.

Jochen Reiser, Mehmet Altintas, Moise Bendayan … (2007)

Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.

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Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

Pazit Beckerman, Jing Bi-Karchin, Ae Seo Deok Park … (2017)

Risk variants of APOL1 associated with human chronic kidney disease have been identified, but causality has been unclear. Transgenic expression in mice now shows that such alleles can indeed cause renal disease.