Bhalla Laboratory
Molecular Physiology of the Kidney

1. Diabetic kidney disease is the most common form of chronic kidney disease in the world, yet no curative therapy is available. Studies of the susceptibility of diabetic kidney disease led to the discovery of differential regulation of endothelial-specific molecule-1, Esm-1 (endocan) in susceptible strains of mice. Esm-1 is a secreted proteoglycan that is enriched in glomerular endothelium and decreases albuminuria in the setting of diabetes and other inflammatory diseases. Ongoing rescue and deletion experiments explore the role of Esm-1 in diabetes and diabetic kidney disease. Studies using single cell analysis inform the biology of select Esm-1(+) vs. Esm-1(-) endothelial cells, and we are currently developing genetic tools to better interrogate the role of local vs. systemic Esm-1 as this would inform potential therapeutic strategies. We also have identified a locus within the gene as a molecular switch for regulation of transcription. 

2. Investigation of the mechanisms of hypertension in the setting of obesity and insulin resistance using renal tubular epithelial insulin receptor deletion challenged the role of insulin in the hypertension of obesity, insulin resistance, and the metabolic syndrome. These studies also shed light on the role of insulin in control of glucose reabsorption via SGLT2. Ongoing studies focus on molecular mechanisms of insulin-regulated SGLT2 and its contrast with insulin resistant pathways in other cell types and tissues. Our current work is focused on post-translational modifications of SGLT2 and their contribution to SGLT2 expression and function.

3. An unexpected finding of aberrant regulation of potassium transport in obesity and insulin resistance has led to another project exploring the role of obesity and insulin in potassium transport in the cortical collecting duct.

4.  A major regulator of sodium reabsorption, Clcnkb, is mutated in humans with Barrter's syndrome, Type 3. However, surprisingly little is known about the regulation of this channel in health and disease. Ongoing experiments include the study of post-translational regulation of Clcnkb surface expression and activity, including glycosylation.

5. Inhibition of sodium reabsorption using diuretics is a mainstay of therapy for hypertension and edema-forming states. Study on the consequences of diuretic therapy using tubular morphometry and single cell approaches, combined balance studies have led to additional work on mechanisms of tubular remodeling in vivo.