Acute injury to the kidney is frequently repaired without long-term consequences, but it can lead to the development of Chronic Kidney Disease (CKD), which manifests as electrolyte abnormalities and hypertension. CKD is a progressive disease that eventually leads to widespread renal fibrosis and renal failure.  In the later stages, CKD patients require dialysis to stay alive. When we disrupted Cullin 3  in the kidney in mice (KS-CUL3^-/-) they developed CKD. We are now working to determine the mechanisms by which disruption of the Cullin Ring Ligase leads to CKD. Our recent data suggest that dysregulation of the cell cycle, resulting in altered cell proliferation, may play an important role. In this project we measure renal function, and determine changes in markers of renal injury by immunofluorescence of kidney sections. We are also beginning “omics” studies to perform global analyses of changes in gene expression and abundances of different proteins to get a complete picture of the early changes occurring after Cullin 3disruption. This will allow us to identify targets of the Cullin Ring Ligase that may contribute to CKD.

In KS-CUL3-/- mice, CUL3 is not completely disrupted as shown by red nuclear signal.  In areas of the kidney lacking CUL3, we detected increased cell proliferation, as shown by PCNA expression (green).

Hypomagnesemia is a serum concentration of Mg²⁺ <1.6mg/dL and is common in hospitalized patients, with a prevalence as high as 65% in ICU patients. It can cause seizures, osteoporosis, and fatal arrhythmias; milder but still significant effects include tremors, pain, and confusion. Hypomagnesemia is also associated with worse outcomes in diabetes, cardiovascular disease, and chronic kidney disease. The distal convoluted tubule (DCT) in the kidney plays a key role in maintaining serum, with most genetic causes of hypomagnesemia affecting this kidney segment.  Hypomagnesemia is very commonly seen together with hypokalemia, which may exacerbate negative outcomes.  Very little is known about how hypomagnesemia affects kidney function, or how hypomagnesemia and hypokalemia interact. Our recent work explores to address this gap in knowledge.  We confirmed previous work that shows that hypomagnesemia decrease NCC levels, and showed that it overrides the effect of hypokalemia to activate NCC. Current work explores mechanisms that may be involved, including changes in intracellular calcium levels and increased NCC ubiquitination.