A recent report by Meena Madhur and colleagues describes a role for lymphocyte adaptor protein (LNK; also known as SH2B3) in angiotensin II (Ang II)-induced hypertension and associated vascular and renal dysfunction. LNK functions as a negative regulator of cytokine signalling and cellular proliferation, but prior to this latest study, how the protein might affect blood pressure (BP) was unknown.

“Our interest in LNK was based on genome-wide association studies that found polymorphisms in LNK to be strongly associated with hypertension as well as autoimmune and cardiovascular disorders,” explains Madhur. “We therefore decided to investigate the role of LNK in hypertension using Lnk−/− mice.”

...LNK might serve as a therapeutic target in the future treatment of hypertension

The researchers first determined the effect of Ang II infusion on BP in their mouse model. Infusion of 490 ng/kg/min Ang II for 14 days resulted in a 35 mmHg increase in systolic BP and profound hypertension (>200 mmHg) in Lnk−/− mice compared to wild-type. Moreover, infusion of 140 ng/kg/min Ang II—a dose that does not raise BP in wild-type mice—resulted in BPs approaching 180 mmHg in Lnk−/− animals.

Renal and vascular infiltration of immune cells was assessed in Lnk−/− and wild-type mice using flow cytometry and immunohistochemistry. At baseline, kidneys from Lnk−/− mice showed increased T-cell infiltration in the renal cortex and medulla compared to wild-type, despite no difference in BP. This effect was also observed in the aorta, and was exacerbated in both by Ang II exposure.

The researchers next transplanted bone marrow from Lnk−/− mice into irradiated wild-type mice, and vice versa, to determine in which cell types loss of Lnk contributes to hypertension. “These experiments showed that loss of Lnk in hematopoietic cells predisposes mice to develop aggravated hypertension, renal inflammation and renal dysfunction,” explains Madhur. “This effect was mediated in part through elevated production of interferon–γ.” Replica analyses in Lnk+/− mice indicated a gene-dosage effect, demonstrating that loss of one allele of Lnk can increase BP and promote renal injury.

The researchers hope to use the Lnk−/− model to further explore the role of the immune system in cardiovascular and renal disorders. “Patients with certain autoimmune disorders have elevated risk of cardiovascular disease,” says Madhur. “Our study provides a 'LNK' between inflammation and cardiovascular disease. Furthermore, LNK might serve as a therapeutic target in the future treatment of hypertension.”