Barani Kumar - Academia.edu (original) (raw)
Uploads
Papers by Barani Kumar
British Journal of Pharmacology, 2019
BACKGROUND AND PURPOSE: Hypertension adversely affects the kidney and is the second leading cause... more BACKGROUND AND PURPOSE: Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II (Ang II) greatly contributes to the progression of hypertensive kidney disease. Ang II has recently been shown to activate signal transducer and activator of transcription 3 (STAT3) in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by Ang II and downstream functional consequences in the kidneys are not fully understood. EXPERIMENTAL APPROACH: C57BL/6 mice were administered Ang II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either AAV expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from 5 patients with hypertension and 5 individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in Ang IIchallenged renal proximal tubular cell line, NRK52E cells. KEY RESULTS: We show that Ang II activates STAT3 in kidney epithelial cells through engaging toll-like receptor 4 and Janus Kinase 2 (JAK2), which is independent of IL-6/gp130 and angiotensin type 1 receptor. Ang II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by small-molecule inhibitor S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. CONCLUSIONS AND IMPLICATIONS: Our study reveals a novel mechanism of Ang IIinduced STAT3 activation in kidney tissues and highlights a translational significance of STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.
British Journal of Pharmacology, 2019
BACKGROUND AND PURPOSE: Hypertension adversely affects the kidney and is the second leading cause... more BACKGROUND AND PURPOSE: Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II (Ang II) greatly contributes to the progression of hypertensive kidney disease. Ang II has recently been shown to activate signal transducer and activator of transcription 3 (STAT3) in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by Ang II and downstream functional consequences in the kidneys are not fully understood. EXPERIMENTAL APPROACH: C57BL/6 mice were administered Ang II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either AAV expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from 5 patients with hypertension and 5 individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in Ang IIchallenged renal proximal tubular cell line, NRK52E cells. KEY RESULTS: We show that Ang II activates STAT3 in kidney epithelial cells through engaging toll-like receptor 4 and Janus Kinase 2 (JAK2), which is independent of IL-6/gp130 and angiotensin type 1 receptor. Ang II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by small-molecule inhibitor S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. CONCLUSIONS AND IMPLICATIONS: Our study reveals a novel mechanism of Ang IIinduced STAT3 activation in kidney tissues and highlights a translational significance of STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.