# Role of the COP9 Signalosome (CSN) in kidney disease and hypertension

> **NIH NIH K01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $131,219

## Abstract

Project Summary / Abstract
Hypertension is the most common risk factor for heart disease and stroke; therefore, it is important to understand
the pathogenesis of hypertension for better prevention and treatment. Rare Mendelian causes of hypertension
identify previously unrecognized physiological pathways and networks, which can illuminate new treatments for
disease. The Mendelian syndrome Familial Hyperkalemic Hypertension (FHHt, or pseudohypoaldosteronism
type II) is a monogenic disease resulting from mutations which increase expression of with-no-lysine kinases
(WNKs). Cullin-RING ligases (CRLs) were recently discovered to regulate blood pressure via proteasomal
degradation of WNKs. Regulation of CRL activity is facilitated by the deneddylase, COP9 Signalosome (CSN),
which binds to the complex and removes the ubiquitin-like protein, NEDD8. A mutation in cullin 3 (CUL3) causes
FHHt and was shown, by in vitro analysis, to have enhanced CUL3 neddylation, increased degradation of the
substrate adaptor kelch-like 3 (KLHL3), and decreased binding to the CSN. We hypothesized that the impaired
interaction with the CSN was integral to the disease. The CSN is a well-studied multi-subunit protein, but the
data here provides the first evidence that disordered CSN activity in the kidney may relate to hypertension and
chronic kidney disease (CKD). The applicant has characterized a genetic mouse model of CSN dysfunction, in
which the catalytic subunit of the CSN, Jab1 is deleted from kidney-tubule cells (KS-Jab1-/-). These mice
developed an unusual phenotype; there was decreased KLHL3 and upregulation of the WNK-SPAK pathway
akin to FHHt, however, several unexpected consequences of Jab1 deletion throughout the nephron were noted
that made the observed phenotype differ from the human disease. This included a decrease in the abundance
of the Na-Cl co-transporter (NCC) after several weeks, and progressive and spontaneous kidney fibrosis,
mimicking chronic kidney disease. Here, the applicant proposes to further explore these provocative results in
three specific aims. Aim 1 will continue to test the hypothesis that impaired CSN function causes FHHt by
generating mouse models that more faithfully mimic the disease mutation. In Aim 2, a combination of in vitro and
in vivo techniques will be used to determine whether the CSN plays a role in modulating NCC directly. Aim 3 will
examine the kidney damage caused by deletion of Jab1. Nrf2 accumulation will be investigated as a possible
mechanism for the damage by generating Jab1 and Nrf2 double knockout mice. In addition to successful
completion of these aims the mentoring and scientific environment make the applicant an ideal candidate to
develop independence in renal physiology research. The proposed research will help reveal the mechanisms
involved in regulation of blood pressure through the CUL3-KLHL3-WNK4 pathway which could lead to
pharmaceutical treatment of hypertension by targeting CRLs, or the CSN. The results ...

## Key facts

- **NIH application ID:** 9890768
- **Project number:** 1K01DK120790-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Ryan J Cornelius
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $131,219
- **Award type:** 1
- **Project period:** 2020-03-02 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890768

## Citation

> US National Institutes of Health, RePORTER application 9890768, Role of the COP9 Signalosome (CSN) in kidney disease and hypertension (1K01DK120790-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9890768. Licensed CC0.

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