Glomerular podocytes play a pivotal role in the pathogenesis of glomerular diseases including diabetic nephropathy(DN). Accumulating evidence suggests that cGMP signaling has podocyte protective effects in kidney diseases. Generation of cGMP is stimulated by nitric oxide (NO) and natriuretic peptides (NPs) such as atrial NP (ANP), brain NP (BNP) and C-type NP (CNP). In podocytes, cGMP generation is potently stimulated by NPs. In contrast, podocytes are minimally responsive to NO. Thus, NPs are the predominant source cGMP generation in podocytes. NPs induce cGMP generation by binding to the NP receptors (NPRs) NPRA (binds ANP and BNP) and NPRB (binds CNP). An important regulator of NP actions is the NP clearance receptor (NPRC), which binds and degrades ANP, BNP and CNP. Pharmacologic blockade of NPRC inhibits binding of NPs to NPRC, which potentiates NPRA- and NPRB-induced cGMP generation. Moreover, NPs have direct podocyte protective actions in vivo because podocyte specific knockout (KO) of the ANP receptor (NPRA) augments glomerular injury in a proteinuric mouse model. Our preliminary studies found that: 1. Podocytes express NPRA, NPRB and NPRC. 2. NPRC is highly expressed in podocytes and significantly limits cGMP generation by locally available NPs. 3. Both ANP and CNP protect podocytes from apoptotic stimuli, 4. Podocyte specific knockout (KO) of NPRC reduces albuminuria in a model of type 1 diabetes (Akita mice), 5. Pharmacologic blockade of NPRC potently promotes podocyte protective cGMP generation in vitro and in vivo, and 6. Pharmacologic blockade of NPRC decreases albuminuria in Akita mice. Based on these observations, we hypothesized that blocking clearance of NPs by NPRC will enhance local NP levels, promote podocyte protective cGMP signaling and ameliorate DKD. Two specific aims are proposed. Aim 1: Examine podocyte specific NPRC KO in DKD. These studies will KO NPRC specifically in podocytes. Subaim 1A will study constitutive NPRC KO in Akita mice. Subaim 1B will complement subaim 1A by studying inducible NPRC KO in Akita mice with established disease. Podocyte protective mechanisms of NP signaling will be studied in kidneys of KO and wild type mice (WT), and in cultured podocytes. Aim 2: Examine pharmacologic blockade of NPRC in Akita mice. Aim 2 will use the ANP analogs ANP(4- 23) and AP811to inhibit NP clearance by specifically binding to NPRC without binding NPRA or NPRB and, in turn, enhance the effects of NPs. We will then study the effects of NPRC blockade in Akita mice. Subaim 2A will determine the most effective drug for further study (proof of concept). Subaim 2B will study Akita mice with established disease. Thus, these studies examine the translational potential of the treatment approach.